Systems and methods for arteriotomy localization

ABSTRACT

A targeting catheter is used to locate an arteriotomy, such as is formed during a femoral artery catheterization procedure. The targeting catheter includes one or more targeting aids, such as an inflatable balloon or sensor (e.g., Doppler or temperature sensor), to locate the arteriotomy. The targeting aid may be positioned at the arteriotomy. An ultrasonic beacon on the catheter may then be located relative to a therapeutic ultrasonic applicator (e.g., by using acoustic time-of-flight) so that the focus of ultrasonic energy from the applicator can be aligned with the arteriotomy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/728,783, filed Oct. 20, 2005 and U.S. Provisional Application No.60/808,665, filed May 26, 2006, both of which are incorporated herein byreference in their entirety.

BACKGROUND

1. Field of the Invention

This disclosure relates to systems of methods for locatingarteriotomies. In some embodiments, the localization is used fortherapeutic targeting (e.g., for targeting of high-intensity focusedultrasound).

2. Description of the Related Art

Certain medical procedures result in bleeding penetration wounds insidethe body, for example via the insertion of devices into blood vesselsand/or organs. Representative procedures include arterial and venouscatheterization for cardiologic or radiologic interventional procedures,needle biopsy procedures, and minimally invasive surgery. Improvedpercutaneous catheterization techniques have enabled physicians toperform an ever-increasing number of diagnostic and therapeuticcardiovascular procedures using devices deployed through arteries andveins. The annual number of therapeutic and diagnostic catheterizationprocedures worldwide is over 14 million and it is continuously growing.

In the vast majority of these catheterization procedures, access to thevasculature is accomplished by percutaneous installation of anintroducer sheath into the common femoral artery. The introducer sheathfacilitates passage of a variety of diagnostic and therapeuticinstruments and devices into the vessel and its tributaries. At theconclusion of the catheterization procedure, the introducer sheath isremoved, leaving an arteriotomy that must be sealed. Arteriotomyhemostasis is most often (approximately two-thirds of all cases)achieved by the application of manual or mechanical compression(standard compression) on the puncture site until a stable clot forms.Several important limitations are associated with the use of standardcompression. For example, a physician, nurse, or trained technician mustapply digital pressure on the access site for up to 40 minutes. Patientsmust remain on bed rest for three or more hours so as not to disruptclot formation in the arteriotomy. The most painful aspects of thecatheterization procedure reported by patients are the standardcompression procedure and lying immobile for hours. The aggressive useof anticoagulants and antiplatelet therapies to prevent thrombusformation during catheterization procedures has greatly increased thedifficulty of sealing the access site using compression. Finally,complications occur, the most frequent of which are the formation ofhematomas, pseudo-aneurysms, and/or arteriovenous fistulae.

Products for sealing arteriotomies based on newer technologies such ascollagen plugs, sealants and mechanical suturing are being successfullymarketed. However, these products are invasive, implant foreignmaterials, require skill and training to use, and can cause majorcomplications. Accordingly, there is a need for improved systems andmethods for sealing arteriotomies

SUMMARY OF THE INVENTION

One embodiment described herein includes an arteriotomy targetingcatheter having an arteriotomy targeting aid coupled to the catheter andadapted to detect the location of an arteriotomy and one or more beaconscoupled to the catheter proximal to the arteriotomy targeting aid. Inone embodiment, the arteriotomy targeting aid comprises an inflatableballoon. In one embodiment, the balloon comprises an elastic polymericmaterial. In one embodiment, the soft elastic polymeric material isselected from the group consisting of one or more of a polyamide, apolyamide blend, a polyethylene, a polyethylene terephthalate, apolyurethane, a polyamide, and a polyamide blend. In one embodiment, thepolyamide blend is PBAX. In one embodiment, the durometer of the balloonmaterial is between 20A and 90D. In one embodiment, the durometer of theballoon material is between 80 A and 65 D. In one embodiment, thedurometer of the balloon material is 90 A. In one embodiment, thearteriotomy targeting aid comprises a mechanical expansible device. Inone embodiment, the arteriotomy targeting aid comprises an arteriotomylocating sensor. In one embodiment, the arteriotomy locating sensorcomprises a temperature sensor. In one embodiment, the temperaturesensor is a thermistor. In one embodiment, the arteriotomy locatingsensor comprises a flow measurement sensor. In one embodiment, thearteriotomy locating sensor comprises an optical sensor. In oneembodiment, the arteriotomy locating sensor comprises an impedancesensor. In one embodiment, the arteriotomy locating sensor comprises aDoppler sensor. In one embodiment, the beacon comprises an ultrasonictransmitter. In one embodiment, the beacon comprises a radio frequencytransmitter. In one embodiment, the beacon comprises a magnetic fieldgenerator.

Another embodiment described herein includes a method of determining thelocation of a therapeutic site in a body, comprising inserting acatheter into the body, wherein the catheter comprises a targeting aid,and manipulating the catheter such that the targeting aid is adjacent toor at the therapeutic site. In one embodiment, the therapeutic site isan arteriotomy. In one embodiment, manipulating the catheter comprisesmoving the catheter until a Doppler signal from the targeting aiddetermines that the targeting aid is adjacent to or at the therapeuticsite. In one embodiment, the targeting aid comprises a temperaturesensor and manipulating the catheter comprises moving the catheter untilthe temperature sensor indicates that it is adjacent to or at thetherapeutic site. In one embodiment, the targeting aid comprises a fluidflow detector and manipulating the catheter comprises moving thecatheter until the fluid flow detector indicates that it is adjacent toor at the therapeutic site. In one embodiment, the targeting aidcomprises an optical sensor and manipulating the catheter comprisesmoving the catheter until the optical sensor indicates that it isadjacent to or at the therapeutic site. In one embodiment, the targetingaid comprises a pressure sensor and manipulating the catheter comprisesmoving the catheter until the pressure sensor indicates that it isadjacent to or at the therapeutic site. In one embodiment, the targetingaid comprises an impedance sensor and manipulating the cathetercomprises moving the catheter until the impedance sensor indicates thatit is adjacent to or at the therapeutic site. In one embodiment, thetargeting aid comprises a force detector and manipulating the cathetercomprises moving the catheter until the force detector indicates that itis adjacent to or at the therapeutic site. In one embodiment, thetargeting aid comprises a mechanically expansive device and the methodcomprises expanding the mechanically expansive device and moving thecatheter until the device is adjacent to or at the therapeutic site. Inone embodiment, the targeting aid comprises an inflatable balloon andthe method comprises inflating the balloon and moving the catheter untilthe balloon is adjacent to or at the therapeutic site. In oneembodiment, the therapeutic site is an arteriotomy created by anintroducer sheath inserted into an artery, inserting the catheter intothe body comprises inserting the catheter and targeting aid through thelumen of the introducer sheath past the arteriotomy and into the artery,and manipulating the catheter comprises retracting the catheter suchthat the targeting aid approaches the arteriotomy. In one embodiment,the introducer sheath is retracted simultaneously with retraction of thecatheter. In one embodiment, the targeting aid comprises an inflatableballoon and wherein the balloon is inflated after insertion of thecatheter and prior to retracting the catheter. One embodiment furtherincludes applying compression above the arteriotomy.

Another embodiment described herein includes a method of determining thelocation of a therapeutic site in a body relative to a therapeuticapplicator, comprising inserting a targeting catheter into the body,identifying the location of the therapeutic site using the targetingcatheter, and determining the position of the targeting catheterrelative to the therapeutic applicator. In one embodiment, thetherapeutic site is an arteriotomy. One embodiment further comprisesaligning the therapeutic applicator with the therapeutic site based onthe relative position of the targeting catheter. In one embodiment,determining the position of the targeting catheter relative to thetherapeutic applicator comprises using triangulation. In one embodiment,the triangulation is based on magnetic fields. In one embodiment, thetriangulation is based on acoustic signals. In one embodiment, thetriangulation is based on an acoustic time-of-flight determination. Inone embodiment, determining the position of the targeting catheterrelative to the therapeutic applicator comprises transmitting anultrasound signal from a transmitter located on the catheter to multiplereceivers located on the therapeutic applicator. In one embodiment, thetransmitter comprises a piezoelectric cylinder. In one embodiment,determining the position of the targeting catheter relative to thetherapeutic applicator comprises determining the acoustic time-of-flightfrom the transmitter to the receivers. In one embodiment, determiningthe position of the targeting catheter relative to the therapeuticapplicator comprises transmitting ultrasound signals from multipletransmitters located on the therapeutic applicator to a receiver locatedon the catheter.

Another embodiment described herein includes a method for sealing avascular opening in a blood vessel, comprising transiently substantiallyoccluding the blood vessel, applying energy adjacent to the vascularopening such that the opening is sealed, and removing the blood vesselocclusion. In one embodiment, the blood vessel is a fermoral, brachial,or radial artery. In one embodiment, the blood vessel is transientlyfully occluded. In one embodiment, occluding the blood vessel comprisesapplying compressive force to the blood vessel. In one embodiment, thecompressive force is applied using an energy applicator that is used toapply the energy. In one embodiment, the compressive force is applied tothe surface of skin located over the blood vessel. In one embodiment,applying energy adjacent to the vascular opening comprises directingenergy from an energy applicator located on or near the surface of skinover the blood vessel. In one embodiment, applying energy to thevascular opening comprises energizing an energy applicator positionedinside a patient near the vascular opening. In one embodiment, theenergy applied is acoustic energy. In one embodiment, the energy appliedis high intensity focused ultrasound energy. In one embodiment, theenergy applied is radio frequency energy. In one embodiment, the energyapplied is microwave energy. In one embodiment, the energy applied isoptical energy. In one embodiment, the optical energy comprises one ormore of ultraviolet, visible, near-infrared, or infrared energy. In oneembodiment, the energy is thermal energy. In one embodiment, the energyis cryogenic energy.

Another embodiment described herein includes a method for sealing avascular opening in a blood vessel in a patient, comprising inserting atargeting catheter into the blood vessel, locating the vascular openingusing the targeting catheter, aligning a therapeutic energy applicatorrelative to the targeting catheter, initiating a station keepingalgorithm configured to detect relative motion between tissue in thevicinity of the vascular opening and the applicator, and applying energyfrom the applicator to tissue adjacent to the vascular opening to sealthe opening. In one embodiment, inserting the targeting cathetercomprises inserting the catheter through the vascular opening. In oneembodiment, the vascular opening is created by insertion of anintroducer sheath and inserting the targeting catheter comprisesinserting the catheter through the sheath. In one embodiment, locatingthe vascular opening comprises manipulating the targeting catheter untila targeting aid on the catheter is adjacent to or at the vascularopening. In one embodiment, aligning the therapeutic energy applicatorcomprises detecting the position of the applicator relative to a beaconlocated on the catheter. In one embodiment, detecting the position ofthe applicator relative to the beacon comprises emitting an ultrasonicsignal from the beacon to multiple receivers on the applicator. In oneembodiment, the energy is high intensity focused ultrasound. Oneembodiment includes withdrawing the catheter from the blood vessel priorto applying energy from the applicator. In one embodiment, the targetingcatheter remains in the patient's body during application of the energy.In one embodiment, the targeting catheter is removed from the patient'sbody prior to application of the energy. One embodiment includesapplying pressure to the blood vessel to transiently partially or fullyocclude the vessel prior to initiating station keeping.

Another embodiment described herein includes a method of detectingtissue movement relative to an ultrasound applicator, comprisingemitting first ultrasonic pulses from at least three ultrasoundtransducers to a target point in the tissue, detecting first ultrasonicechoes with the ultrasound transducers, emitting second ultrasonicpulses from the ultrasound transducers, detecting second ultrasonicechoes with the ultrasound transducers, comparing the first and secondultrasonic echoes, and determining the amount of relative tissuemovement using the comparison and directional vectors between theultrasound transducers and the target point. In one embodiment,comparing the first and second ultrasonic echoes comprises determiningtime shifts between the echoes. In one embodiment, comparing the firstand second ultrasonic echoes comprises determining phase differencesbetween the echoes. In one embodiment, determining the amount ofrelative tissue movement comprises executing a recursive algorithm. Inone embodiment, experimentally determining the directional vectors.

Another embodiment described herein includes a method of detectingtissue movement relative to an ultrasound applicator, comprisingemitting a first ultrasonic pulse from a first ultrasound transducer toa target point in the tissue, detecting a first ultrasonic echo at asecond and third ultrasound transducer, emitting a second ultrasonicpulse from either the second or third ultrasound transducer to thetarget point, detecting a second ultrasonic echo at the first ultrasoundtransducer and the non-transmitting second or third ultrasoundtransducer, comparing the echoes to previously recorded echoes, anddetermining the amount of relative tissue movement using the comparisonand directional vectors between the ultrasound transducers and thetarget point. One embodiment includes detecting the first and secondultrasonic echoes at at least one additional ultrasound transducer. Inone embodiment, comparing the echoes comprises determining time shiftsbetween the detected echoes and the previously recorded echoes. In oneembodiment, comparing the echoes comprises determining phase differencesbetween the detected echoes and the previously recorded echoes. In oneembodiment, determining the amount of relative tissue movement comprisesexecuting a recursive algorithm. One embodiment includes experimentallydetermining the directional vectors.

Another embodiment described herein includes a method of detectingtissue movement relative to an ultrasound applicator, comprisingemitting an ultrasonic pulse from a first ultrasound transducer to atarget point in the tissue, detecting an ultrasonic echo at the firstultrasound transducer and at a second and third ultrasound transducer,comparing the echo to a previously recorded echo, and determining theamount of relative tissue movement using the comparison and directionalvectors between the ultrasound transducers and the target point. Oneembodiment comprises detecting the ultrasonic echo at at least oneadditional ultrasound transducer. In one embodiment, comparing the echocomprises determining time shifts between the detected echo and thepreviously recorded echo. In one embodiment, comparing the echocomprises determining phase differences between the detected echo andthe previously recorded echo. In one embodiment, determining the amountof relative tissue movement comprises executing a recursive algorithm.On embodiment includes experimentally determining the directionalvectors.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an ultrasound applicator and a visualization of thefocused, high intensity ultrasound emitted from the applicator.

FIGS. 2A-2C are micrographs of femoral arteriotomies sealed with focusedultrasound. FIG. 2A illustrates a sealed ovine femoral artery. FIG. 2Billustrates a sealed swine femoral artery. FIG. 2C illustrates the sameartery as FIG. 2B, but viewing it from the intimal surface.

FIG. 3 is a perspective view of an acoustic hemostasis system.

FIG. 4A depicts a hand-held therapeutic applicator being positioned ontoa patient.

FIG. 4B is an illustration of the user interface screen located on thehand-held therapeutic applicator.

FIG. 5 is a flowchart depicting one embodiment of an overall systemvascular closure procedure.

FIG. 6 is a diagram of an introducer sheath located in an femoralartery.

FIG. 7A is a diagram of a vascular closure procedure illustrating theinsertion of a targeting catheter into a vessel through an introducersheath.

FIG. 7B is a diagram of a vascular closure procedure illustrating theinflation of a targeting balloon and compression from a therapeuticapplicator.

FIG. 7C is a diagram of a vascular closure procedure illustratingarteriotomy localization.

FIG. 7D is a diagram of a vascular closure procedure illustratingalignment of a therapeutic applicator to the arteriotomy.

FIG. 7E is a diagram of a vascular closure procedure illustratingcompression applied to either partially occlude or fully occlude theartery prior to focused energy treatment.

FIG. 7F is a diagram of a vascular closure procedure at the initiationof station keeping.

FIG. 7G is a diagram of the vascular closure procedure illustrating thewithdrawal of the targeting catheter from the artery.

FIG. 7H is a diagram of the vascular closure procedure illustrating thedosing of the focused ultrasound in order to perform acoustic arterialhemostasis.

FIG. 8 is a perspective view of a balloon targeting catheter.

FIG. 9 is a diagram of the balloon targeting catheter and associatedcomponents.

FIG. 10A is a longitudinal cross-sectional view of the distal section ofa balloon targeting catheter.

FIG. 10B is an axial cross-sectional view of the distal section of aballoon targeting catheter.

FIG. 10C an end view of the distal section of a balloon targetingcatheter.

FIG, 10D is a longitudinal cross-sectional view of the distal section ofa balloon targeting catheter.

FIG. 11 is a diagram illustrating the targeting catheter and ultrasoundapplicator after arterial localization with the arteriotomy locatingbeacon emitting ultrasound waves.

FIG. 12 is an illustration of the user interface for targeting on thearteriotomy.

FIG. 13 is a schematic illustrating acoustic time of flight targeting ofthe therapeutic applicator.

FIG. 14 is a schematic of a cylindrical piezoelectric arteriotomylocating beacon having three possible modes of operation.

FIG. 15 is a schematic of a therapeutic applicator face having CW/PWDoppler mode transducers, ATOF receivers, and therapeutic transducers.

FIG. 16 is a graph showing voltage measured on a piezoelectric elementfrom external stress (hard surface).

FIG. 17 is a graph showing voltage measured on a piezoelectric elementfrom external stress (thumb).

FIG. 18 is a graph showing the accuracy of station keeping detectedmovement in the X-axis using a pitch-catch algorithm.

FIG. 19 is a graph showing the accuracy of station keeping detectedmovement in the Y-axis using a pitch-catch algorithm.

FIG. 20 is a graph showing the accuracy of station keeping detectedmovement in the Z-axis using a pitch-catch algorithm.

FIG. 21 depicts three graphs showing station keeping detected motiontional approach for elevation rotation.

FIG. 22 depicts three graphs showing station keeping detected motiontional approach for roll rotation.

FIG. 23 depicts three graphs showing station keeping detected motion eapproach for elevation rotation.

FIG. 24 depicts three graphs showing station keeping detected motion eapproach for roll rotation.

FIG. 25 depicts three graphs showing the accuracy of station keeping entusing a calculated direction matrix along the X-axis, Y-axis, andZ-axis,

FIG. 26 depicts three graphs showing the accuracy of station keepingdetected movement using a measured direction matrix along the X-axis,Y-axis, and Z-axis, respectively.

FIG. 27 is a block diagram showing a station keeping system.

FIG. 28 is a schematic depicting a transucer concept that uses threephased arrays to multiple points along the z-axis.

FIG. 29 is a flow chart depicting a Radio Frequency Ultrasound MotionEstimate algorithm for station keeping.

FIG. 30 is an illustration of an ultrasound appliactor user interfaceduring therapeutic dosing.

FIG. 31 is an illustration of a targeting catheter having apiezoelectric Doppler device as a targeting aid.

FIG. 32 is a schematic of a targeting catheter located in a femoralartery.

FIGS. 33A-33C are illustrations of a user interface on the therapeuticapplicator.

FIG. 34 is a schematic illustrating the determination of the distancebetween an arteriotomy and a beacon/arteriotomy sensor.

FIG. 35 is a block diagram of an arteriotomy locating system.

FIG. 36 is a schematic of a forward looking Doppler arteriotomy locatingsensor.

FIG. 37 is a schematic of a side looking Doppler arteriotomy locatingsensor.

FIG. 38 is a schematic of a Z-matching arteriotomy locating sensor.

FIG. 39 is a schematic of a TDTM probe having a single thermistor at itstip.

FIG. 40 is a graph of temperature signals from a thermistor bead on aTDTM probe.

FIG. 41 is a graph of temperature signals from a thermistor bead on aTDTM probe while bleeding is simulated using dropwise flow pulses.

FIG. 42 is a schematic of a TDTM probe having a single thermistor at itstip under pulsatile flood flow.

FIG. 43A is a graph of temperature differential measured fromexperimental setup of FIG. 42 while the TDTM probe bead is moved fromthe lumen of the femoral artery into the puncture track.

FIG. 43B is a graph of temperature differential measured fromexperimental setup of FIG. 42 while the TDTM probe bead is moved fromthe puncture track under maximal compression (no track bleeding)conditions directly to the lumen of the femoral artery.

FIG. 44 is a schematic of a TDTM probe having dual thermistor beads nearits tip under in vivo pulsatile blood flow conditions.

FIG. 45 is a graph of temperature signals from the TDTM probe of FIG.44. The TDTM probe is moved from the positions of both beads located inthe lumen to both beads in the puncture track.

FIG. 46 is a schematic of a TDTM probe having three thermistor beadsnear its tip.

FIG. 47 is a graph of temperature differentials measured from a TDTMprobe with dual beads in response to therapeutic energy test powerpulses delivered from a focused ultrasound applicator.

FIG. 48 is a schematic of a TDTM probe having two thermistors inconjunction with a non-thermistor partner sensor.

FIG. 49 is a schematic of a TDTM probe used in conjunction with aninvasive cautery or puncture sealing device.

FIG. 50 is a schematic of an experimental setup for measuring theeffects of transient arterial occlusion.

FIG. 51 is a photograph of the setup depicted in FIG. 50.

FIG. 52 is a graph of temperature change during heating of theexperimental setup of FIG. 50 and 51.

FIG. 53 is a photograph of the cross-section of the artery treated inthe experiment of FIG. 50-52.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

Disclosed herein are systems and methods associated with an acoustichemostasis device. This device, designed for rapid, noninvasive sealingof femoral arteriotomies using focused ultrasound technology, requiresneither the prolonged application of pressure and immobilizationassociated with standard compression, nor implantation of any foreignmaterial. Thus, this system has the potential to provide a superiormethod of arteriotomy closure. This system has been also described inU.S. Pat. No. 6,656,136, filed Oct. 25, 2000; co-pending U.S.application Ser. No. 10/671,417 filed Sep. 24, 2003; U.S. Pat. No.6,719,694, filed Dec. 22, 2000; and U.S. Pat. No. 6,626,855, filed Nov.22, 2000; all of which are incorporated herein by reference in theirentirety.

Because of its unique properties in soft tissue, medical ultrasound canbe brought to a tight focus at a distance from its source. FIG. 1depicts an ultrasound applicator 20 emitting focused ultrasound to afocal volume 5. The ultrasound energy is modeled using the Schlierentechnique. FIG. 1 illustrates the ability to tightly focus ultrasoundwaves in soft tissue at a distance from its source. If sufficient energyis radiated from an ultrasound source (e.g. ultrasound applicator 20),tissue located in the focal volume 5 can be rapidly heated whileintervening and adjacent tissues are unaffected. By preciselycontrolling the magnitude, location and distribution of the focusedultrasound, noninvasive therapies such as arterial puncture sealing canbe rapidly and safely administered.

Animal and human studies have show that use of high-intensity focusedultrasound to locally heat punctures and lacerations in arterial andvenous walls can affect rapid and durable sealing (acoustic hemostasis)of these wounds.

The acoustic hemostasis sealing mechanism relies not on bloodcoagulation, but rather on the formation of a thermally coagulatedcollagen cap that adheres to the external elastic lamina and therebyseals the arteriotomy. This method of arteriotomy closure isnoninvasive, acts on collagen naturally present in the adventitial andperivascular tissues, is unaffected by periprocedural anticoagulationtherapy, is effective over a spectrum of wound and vessel sizes, andoccurs in a matter of seconds.

In some embodiments, successful acoustic hemostasis treatment ispromoted by: (1) adequate compression of the arteriotomy to obviatebleeding, and the consequential convective heat loss, during energydelivery, and to approximate the edges of the arteriotomy; (2) accuratespatial targeting of the ultrasound energy on the arteriotomy site; and(3) sufficient ultrasound energy to coagulate (denature) native collagenin the adventitial and perivascular tissues. In some embodiments, theultrasonic systems described herein are designed to satisfy each ofthese requirements over a diverse patient population and to do so whileaccommodating the varying skill levels of users.

In some embodiments, the ultrasonic system is intended for noninvasivelysealing femoral arteriotomies and reducing time to hemostasis,ambulation and eligibility for hospital discharge in subjects who haveundergone diagnostic or interventional catheterization procedures usingan 8 French or smaller introducer sheath. However, the system may alsobe used for other purposes, with other subjects, and othercatheterization procedures.

In some embodiments, the system and methods described herein may be usedwith other energy sources besides ultrasound sources. For example, insome embodiments, a radio frequency, microwave, optical, or thermaltherapeutic applicator may be used. In some embodiments, the opticalapplicator may provide one or more of ultraviolet, visible,near-infrared, or infrared energy. In various embodiments, the thermalapplicator may provide heating or cryogenic energy.

Histopathological examinations of extirpated ovine and porcine arteriestreated with varying doses (i.e., intensity and duration of exposure) offocused ultrasound that exceeded the threshold dose for arteriotomysealing were performed to elucidate the healing pathway subsequent toacoustic hemostasis. Generally, within 14 days post catheterizationusing a 5F introducer sheath, the blood clots that form in thearteriotomy, adventitia and perivascular tissue were infiltrated withspindle-shaped transformed smooth muscle cells that produced collagenmatrix. There was minimal to mild neointimal proliferation lining thelumen of the artery in the areas of trauma from the catheter puncture,and the neointima was covered by intact endothelium with no evidence ofmural thrombus formation in the treated areas.

The arteries examined 30 days following the acoustic hemostasisprocedure were completely healed. The neointima was well organized,covered by intact endothelium, and increased only a minimal amount fromthe thickness at 14 days post treatment. Neovascularization of thehealed tissue and neointima was more prominent than at 14 days andappeared to be stabile by 60 days post treatment.

At 60 days following catheterization, the arteries were completelyhealed and quiescent. The neointima was stabile, covered withendothelium and no longer proliferating. There was no morphologicalevidence of vessel wall weakness resulting from the focused ultrasoundexposure.

FIGS. 2A-2C illustrate microscope photographs of femoral arteriotomiessealed with focused ultrasound and then extirpated within 30 minutes oftreatment. FIG. 2A is a cross-sectional photograph of an ovine femoralartery. The arteriotomy is sealed by formation of a coagulated collagencap 10 on the external elastic lamina 12. An acute fibrin clot 14 withtrapped coagulated red blood cells forms under the collagen cap andextendes partially into the vessel lumen 16. The intrinsic fibrinolyticsystem prevents these clots from expanding into the lumen and occludingit with an acute thrombus. FIG. 2B is a photograph of a swine femoralartery illustrating that ultrasound-induced coagulaum 18 completelycovers the arteriotomy site (adventititial surface of artery) forming arobust membrane that seals the wound. FIG. 2C illustrates the samearteriotomy as FIG. 2B, but viewing it from the intimal surface. (Thefibrin clot has been extracted to facilitate visualization of thermallycoagulated native collagen.) Note that the coagulum typically fillsabout 20% of the thickness of the arterial wall from the adventitialsurface.

In some embodiments the ultrasonic systems described herein may be acompact, mobile, self-contained, therapeutic ultrasound system. In someembodiments the ultrasonic system comprises four major components:applicator, generator, targeting catheter, and disposable patientinterface (DPI). FIG. 3 illustrates one such compact system having agenerator 24 on a movable cart that is connected to a hand-heldultrasound applicator 20.

The applicator may be a handheld device that comprises an ergonomicplastic housing, a display with graphical user interface, and amultiplicity of transducers that facilitate treatment targeting,maintenance of proper arteriotomy compression during treatment, anddelivery of focused ultrasound sufficient to seal the arteriotomy. Asillustrated in FIG. 4A, the hand-held applicator 20 may be convenientlyhandled by a physician during the procedure for applying compression andproperly positioning the ultrasound transducers relative to thearteriotomy. The applicator 20 may include a display 25 such as depictedin FIG. 4B to provide compression and/pr targeting feedback to the user.Although in one embodiment, the applicator provides therapeuticultrasound, other therapeutic applications may be used (e.g., providinglaser, rf, microwave, or heat energy for therapeutic use).

The generator may include a power supply; a central processing unit andoperating system; and the hardware and software modules that enable theuser interface, targeting, compression-monitoring, dosimetry,focused-ultrasound-energy-delivery and station-keeping functions. Thegenerator may also provide a means to transport and maneuver the system,and to store the applicator when not in use.

The targeting catheter may include any catheter having one or moretargeting aids for locating and targeting the arteriotomy. The targetingcatheter may be placed down the lumen of the procedure introducer sheathor inserted in any other fashion into an artery containing anarteriotomy. In various embodiments, the targeting aid may include aninflatable balloon, force detectors, optical sensors, pressure sensors,impedance sensors, mechanically expansive devices, temperature sensors(e.g., thermisters), and/or Doppler sensors. In one embodiment, thetargeting catheter features an arteriotomy locator beacon (e.g., a smallultrasound transducer) in addition to the targeting aid(s). The beaconmay be used to determine the location of the beacon and/or targetingaids in reference to the therapeutic applicator. In one embodiment, thebeacon is located in the catheter shaft and slightly proximal to aballoon and transmits ultrasonic pulses that serve to signal itsposition relative to the applicator.

The disposable patient interface, DPI, is a sterile, single-use,polymeric device that envelops the applicator and is designed tomaintain the sterile field and serves as an acoustic coupling mediumbetween the applicator and the patient's skin. Some examples of asuitable DPI are described in more detail in U.S. ApplicationPublication No. 2005-0215901, filed Jan. 18, 2006, which is incorporatedherein by reference in its entirety.

FIG. 5 is a flow chart illustrating the procedural steps for one methodof performing acoustic arterial hemostasis. It will be appreciated that,depending on the embodiment, some steps may be removed or added or maybe conducted in an order different from that indicted above. Each stepis described in more detail below. It will also be appreciated thatthese steps may be used for any treatment involving focusing energy to atreatment site and not just for closing an arteriotomy.

At block 100 in FIG. 5, a targeting catheter is inserted to aid in thelocalization of an arteriotomy or other site where treatment is desired.In embodiments where a femoral arteriotomy is to be treated, theacoustic targeting catheter may be placed into the femoral arterythrough an introducer sheath prior to ultrasonic treatment. In oneembodiment, this targeting catheter comprises a guidewire like devicehaving one or more features that enable the catheter to locate anarteriotomy (e.g. using an inflatable balloon, force detectors, opticalsensors, pressure sensors, impedance sensors, mechanically expansivedevices, temperature sensors, and/or Doppler sensors), report theposition of the arteriotomy relative to the therapy delivery device(e.g., using beacon such as an ultrasonic beacon), and/or measure bloodflow properties (e.g., using sensors to measure blood velocity,volumetric flow rates, pressure, etc.).

FIG. 6 is a schematic illustrating a percutaneous catheterizationprocedure which involves insertion of an introducer sheath 26 into thefermoral artery 28. When the sheath is removed, the resultingarteriotomy 30 must be sealed to prevent hemorrhage. FIG. 7A is aschematic illustrating the insertion of a targeting catheter 32 throughthe introducer sheath 26 located in the femoral artery 28. Also depictedin the schematic is the intervening tissue 30 through which the sheath26 extends. The targeting catheter 32 includes a targeting aid 34 (e.g.,an inflatable balloon), a beacon 36, and a soft flexible tip 37 at theend of the targeting catheter 32. However, is should be noted thattargeting catheters containing other features described herein may beused.

In one embodiment, the targeting catheter 32 includes a sterile,single-use, balloon catheter that is placed down the lumen of theprocedure introducer sheath. FIG. 8 depicts a targeting catheter 32having an inflatable balloon 34 (shown inflated) as a targeting aid anda beacon 36 (e.g., an ultrasound transducer located within the cathetershaft and slightly proximal to the balloon). As described in more detailbelow, the balloon 34 may be used to locate the arteriotomy. The beacon36 may then be used to signal its position relative to the applicator,for example, by transmitting ultrasonic pulses.

In some embodiments, the catheter outside diameter is less than 4 French(1.33 mm). Thus, in some such embodiments, the beacon 36 is amicro-beacon with an outside diameter is less than 1.33 mm. In variousembodiments, the beacon 36 may pass position information from insidehuman body to an external system using either an electromagnetic methodor a mechanical (e.g. acoustic) method. Provided below is a descriptionof an ultrasound beacon and an electromagnetic beacon suitable for useas described herein.

An ultrasound beacon 36 may be made from piezo-ceramic material (e.g.,one or more ultrasonic transducers). The ultrasound beacon 36 can eitherwork in transmitter mode, in which the beacon 36 transmits an ultrasoundwave when an RF electrical source is applied on its surface, orreceiving mode, in which the beacon 36 generates an electrical RF signalwhen a mechanical wave hits its surface. An acoustic time of flight(ATOF) system may used to detect the beacon 36 position inside a humanbody (as described in more detail below with respect to block 204 ofFIG. 5).

In one embodiment, the beacon 36 in the ATOF system can be apiezo-ceramic tube, which may have an outside diameter of about 1 mm andproduces an ultrasound wave around 1.3 MHz when using a hoop vibrationmode. The beacon's 36 position on the catheter may be designed to be ata known and repeatable spatial relationship relative to the targetingaid 34 (e.g., a specified distance from the edge of a targeting balloon,which can be positioned to touch the arteriotomy when inflated insidethe artery).

Although an ultrasonic beacon system has been described, it will beappreciated that any beacon system that can be fit into the desiredbiological system (e.g., artery) may be used to detect the position ofthe beacon, and consequently, the position of the targeting aid (e.g.,balloon). For example, an electromagnetic sensor, such as microbars(available from Ascension Technology Corporation, Burlington, vt.), anda 3D space tracking system may achieve the same result as an ultrasonicbeacon used in conjunction with ATOF methods.

FIG. 9 is a schematic depicting an overview of the components that maybe directly associated with a balloon targeting catheter as describedabove. The catheter 32, balloon 34, floppy distal tip 37 and beacon 36may be attached by way of a flexible body tube to a hub 42 that providesfor interconnections to electrical drive and inflate/deflate functions.

The beacon 36 may be electrically coupled to a cable 44, which may bestrain relief mounted into the hub 42. There is optionally an electricalmatching component or network 46 inside the hub that transforms animpedance to improve electrical efficiency of the system and/or pulseshape transmitted by the beacon. Additionally there may be an electricalconnector 60 on the terminus end of the cable.

Syringes 48 and 50 and their associated valves 52 and 54 may be used forfluid (e.g., sterile saline) injection and removal (e.g., to prime theballoon prior to use and to inflate and deflate the balloon after it hasbeen inserted into the artery). Alternatively, a multi-port devicedesigned for one-handed operation may be used. For example, fluidmanagement devices that are spring loaded may be used, permittingrelease of the balloon fill by pushing one button.

The system may also include pressure gauge 56 to monitor or control thepressure or volume in the balloon. Those of skill in the art willrecognize that pressure gauge 56 may be representative of any component(or various components) that achieves the effect of monitoring orcontrolling the pressure or volume in the balloon. It may also beadvantageous to provide for a pressure regulation or release when theartery is fully compressed. This ability protects both the arterial walland the balloon from compressive damage and can facilitate a moreaccurate location of the beacon 36 at the arteriotomy site throughoutthe compression sequence.

An insertion tool 58 may be provided to facilitate insertion of thedistal tip 37 of the catheter 32 into an introducer sheath alreadyinserted into a patient's artery. The insertion tool 58 may have atapered distal tip suitable to be inserted into and to open thehemostatic valve on the introducer sheath (see FIG. 6) and has aconstriction in its internal bore proximal to the location of theballoon that restricts bleeding through the device. This restriction maybe designed to have a close fit to the diameter of the catheter body butstill allow for free movement. In one embodiment, a close fit may beprovided using a soft elastomeric material, thus providing a sealingfunction.

FIG. 10A, 10B, 10C, and 10D illustrate the design and construction ofthe distal section of one embodiment of a balloon targeting catheter inmore detail. Referring to FIG. 10A, the catheter is substantially acoaxial design. Balloon 34 may be any suitable pliable material. In oneembodiment, balloon 34 is made of soft, elastic polyurethane of aDurometer between 80A and 65D. The balloon 34 may be nominally between 3and 7 mm in diameter. In some embodiments, the shape of the balloon 34is not optimally spherical but rather a modified sphere foreshortened inits axial dimension in order to provide a large “footprint” against theartery wall but not to fully occlude blood flow in the artery. Theseshape variations may be accomplished using one of two methods, which maybe used singly or in combination with one another. In one embodiment,the balloon may be foreshortened by locating the distal attach point 62closer to the proximal attach point, thus “pooching” in the balloon.This “pooching” creates a non-spherical distal end for the balloon.Additionally, the neck of the balloon may be mounted to the core tube 64in an inverted manner wherein the mounting point is effectively insidethe balloon. The advantages of this inverted mounting technique include:i) allowing for a larger “footprint” against the artery wall and ii)mounting the balloon ends effectively inside the balloon allows thepiezoelectric beacon to not have a layer of bonded balloon materiallocated between it and the patient, thereby allowing for improvedacoustic transmission properties.

Alternatively, the balloon 34 may be fabricated from stiff, essentiallyinelastic materials such as polyester or PET. These balloons hold aninflated shape more consistently than the polyurethane balloons andrequire/tolerate much higher inflation pressures. In some embodiments,unfold and refold characteristics may be tailored such that upondeployment, a smooth contact with the elements of the vessel ispresented.

In some embodiments, the catheter may include a core tube 64. The coretube 64 may provide structural stiffness longitudinally, assuringintegrity of the catheter assembly. In addition, the core tube 64provides one or more internal lumens in which fluid can be transportedto/from the balloon, and, with a diameter less than the overall body 66diameter, provides a place where the deflated balloon may nest duringinsertion and removal. As depicted in the cross-sectional view of FIG.10B, the core tube 64 may include two lumens (e.g., in a “double-D”configuration). One lumen may be used for fill and the other forventing, thus facilitating quick priming and removal of air bubbles.(Note that the holes in the core tube inside the balloon are not shownon of FIG. 10A through 10D.) The core tube is advantageously made of ahigher Durometer (e.g. 55D to 75D) polyurethane that is compatible withbeing thermally bonded to other components in the catheter, mostimportantly the balloon 34.

Further describing the design, core tube 66 passes through the insidediameter of cylindrical beacon 36 and is terminated and interconnectedat the hub 42 (see FIG. 9). It is advantageous to provide an enhancedflexibility of the catheter at that point immediately distal to thelocation of the beacon (and immediately proximal to the balloon) asdepicted as section 68 on FIG. 10A. This location is also that of thethermal bond mounting the balloon to core tube 64. This flexibilitypermits the balloon to more flatly locate to and seal the arteriotomyeven as the catheter is being pulled up at the angle of the entrychannel (or track).

Proximal to the beacon 36, the core tube 66 may be positioned within abody tube 70, which may have an about 1 mm outside diameter and be madefrom polyurethane. Use of polyurethane promotes thermal bonding andmelding with a jacket that covers beacon 36.

FIG. 10B is a rendering of the distal cross-section of a balloontargeting catheter from a view proximal to the beacon location. Thisview also depicts the location of wires extending through the catheterto the beacon 36. FIG. 10C depicts an end view of the distal end of theballoon targeting catheter showing the core tube 64 in cross-section.FIG. 10D depicts a cross-sectional view longitudinally through thedistal portion of the balloon targeting catheter.

Returning to the discussion of the flow chart in FIG. 5, at block 102,after insertion of the targeting catheter, the balloon 34 is inflatedonce its position is known to be past the arteriotomy 30. FIG. 7Bdepicts the inflation of the balloon 34 within the artery 28 beyond thedistal opening of the introducer sheath 30. The balloon 34 may beinflated with any suitable fluid such as a liquid (e.g. a sterile salinesolution). The user next (or simultaneously) applies compression withthe applicator 20 to stop blood flow in the tract 33 through the tissue31 that is formed by the introducer sheath 26.

At block 104 in FIG. 5, the introducer sheath 26 and targeting catheter32 are retracted from the artery 28 as a unit until the balloon 34 comesinto contact with the vessel wall at the arteriotomy site 30 (FIG. 7C).In this position, egress of blood from the artery through the tract 33is impeded by the balloon 34 and the arteriotomy locator beacon issituated within the arteriotomy. Thus, by retracting the balloon untilit contacts the artery 28 wall, the arteriotomy site 30 is localized.

Next, at block 106 of FIG. 5, the pressure applied to the applicator 20may be released so as to allow for easier alignment of the applicator 20relative to the arteriotomy 30 as illustrated in FIG. 7D. The targetingaid balloon 34 will serve to stop blood flow up the track 33 during thisprocess. A cluster of receivers in the applicator may be used to detectultrasonic pulses transmitted from the arteriotomy locator beacon 36 andtargeting algorithms resident in the generator may continuously analyzethese signals and produce graphical feedback on the applicator 20display (e.g., utilizing acoustic time of flight (ATOF) algorithms).Using this intuitive information, the user is enabled to quickly andaccurately target the focused ultrasound at the arteriotomy site 30.

As noted, acoustic Time-of-Flight (ATOF) may be utilized to determinethe position of the beacon 36 relative to the therapeutic applicator 20.In some alternative embodiments, a separate beacon is not included onthe targeting catheter (for example, where the arteriotomy targeting aidis capable of ultrasound generation, such as when it is a Doppler beaconor a resistance heated PZT). In such embodiments, the targeting aid ineffect also serves as the acoustic beacon. Accordingly, the ATOF methodsdescribed herein can also be used in these alternative embodiments.

The PZT element (either in beacon 36 or as part of the targeting aid 34)may be utilized as a highly localized sound source marker, easilyvisible in an ultrasound image or detected and localized in an AcousticTime of Flight detection system. In one ATOF approach, the beacontransmits tone bursts of sound to receivers encircling the outerperimeter of the therapeutic applicator. The in-situ beacon is pulsedwhile each of the receivers independently measures the time for thepulse to arrive. When the time of flight to each receiver is known andthe time has been converted to a distance between the beacon and thereceiver, then the position of the beacon relative to the receivers canbe calculated using triangulation. A minimum of three receivers may beused to calculate the X, Y and Z position of the beacon relative to theTherapeutic Applicator. If more than three sensors are used, theaccuracy of the position calculation can be improved.

By continuously monitoring the position of the arteriotomy relative tothe therapeutic applicator via ATOF, the user can adjust the positionand orientation of the applicator such that the therapeutic energysource focus (e.g., laser, RF, ultrasound, or microwave) is located atthe arteriotomy. In some embodiments, the user interface may provide adisplay to assist the user in appropriately adjusting the position andorientation of the applicator. The display may include graphicalelements such as cross hairs or target circles as well as ultrasoundimages of the focal region. Those of skill in the art will appreciatemany possibilities for providing feedback to a user to assist inaligning a therapeutic energy source with the arteriotomy locatingsensor on the Targeting Catheter.

FIG. 11 illustrates the applicator 20 positioned over the arteriotomywith the targeting catheter positioned such that the arteriotomylocating beacon 36 are positioned at the centroid of the arteriotomy.Waves 74 depicted in the illustration represent acoustic energy from thebeacon 36 in which the ATOF measurement is performed via acousticsensors on the therapeutic array located on the applicator 20. FIG. 12illustrates one embodiment of a user interface 78 for targeting on thearteriotomy. The circle/bullseye 80 represents the position of the focalpoint of the therapeutic applicator and the cross hair 82 represents thelocation of the arteriomety locating sensor as determined by ATOF. Theuser may be instructed to align the bullseye on top of the crosshairsthereby insuring that the arteriotomy is within the focus of thetherapeutic applicator.

Target localization based on acoustic time of flight (ATOF) can provideaccurate and robust position sensing of target location relative to thetherapeutic ultrasound transducer. Direct X, Y and Z (i.e.three-dimensional) coordinate locations of the target can be providedwithout the need for image interpretation. Three-dimensional targetinginformation facilitates the use of an explicit user interface to guideoperator actions. ATOF is less sensitive to variations in patientanatomy as compared to imaging techniques. ATOF can be accomplished witha relatively simple and inexpensive system compared to the compleximaging systems used by alternate techniques. In some embodiments,continuous tracking of the target in the presence of movement betweenthe target and the external transducer may be provided. In someembodiments, ATOF allows use of system architectures that utilize alarger fraction of the patient contact area to generate therapeuticpower (as contrasted with imaging based alternatives)—thus reducing thepower density applied to the patient's skin.

FIG. 13 illustrates one embodiment of an ATOF system that includes abeacon 36 having a small ultrasonic transmitter 36 such as describedabove placed at or near the arteriotomy site 33 (e.g., through use of atargeting catheter). An array of ultrasound receiver sensors 92generally encircling the outer diameter of the ultrasound therapeutictransducer 90 is located on the applicator. The in-situ transducer(beacon) 36 is pulsed while simultaneously the receivers 92 begin tolisten for the ultrasound pulses to arrive. Each of the receivers 92independently measures the time for the pulse to reach their location.The time of flight from the receiver 92 to the beacon 36 can bedetermined and the location of the beacon 36 can be calculated by usinga variety of triangulation techniques familiar to those skilled in theart of sonomicrometry and/or global positioning systems (GPS). Thehistorical basis for this approach is partially documented in U.S. Pat.No. 4,154,114 to Katz and in U.S. Pat. No. 4,100,916 to King. Veseley,in U.S. Pat. No. 6,019,725, provides a good description of 3D tracking.All of these patents are incorporated herein by reference in theirentirety.

It should be recognized that while embodiments will be described whereinthe beacon 36, as described above, transmits and the receivers 92receive, the transmit and receive functions may be reversed or used inconfigurations wherein various or all sensors both transmit and receive.

It should also be recognized that it may be advantageous to provide forhigher accuracy of position determination at and in the vicinity of thetherapeutic target, while permitting lower resolution in locations offtarget. Such lower resolution may be adequate for providing navigation(positioning of the therapy transducer on the patient) guidance to theoperator.

The transmitting beacon 36 may be “pinged” with a short burst ofapproximately 3 cycles. The frequency of the ultrasound burst requires atradeoff between location sensitivity, signal attenuation, anddispersion angle. Higher frequencies help to improve the accuracy of thelocation data. At lower frequencies the signal may encounter lessattenuation its path to the receivers 92, which will generally produce abetter signal to noise ratio. Also at lower frequencies, the transmitterwill tend to distribute its energy over a wider angle for giventransducer dimensions, which will allow the beam to spread out over awider area to better reach the receivers 92 from a variety of locationsin the targeting space. For an arteriotomy locator, in one embodiment, afrequency in the range of about 500 KHz to about 1 MHz is used,providing good resolution, low attenuation, and compatibility withisotropic transducers that can be inexpensively fabricated.

As noted above, the receiving sensors 92 may be placed in an array, orconstellation, around the therapeutic transducer 90. A minimum of threeelements may be used to allow the position of the beacon 36 to becalculated in 3 dimensions. Additional sensors can be used to improvethe accuracy, robustness and sensitivity of the calculation. The analogsignal from the receivers may be, after pre-amplification, converted todigital format for accurate signal processing. The rate at which thesignal is digitized may influence the maximum accuracy, or precision, ofthe time of flight calculation. The precision is determined by the speedof sound in human tissue, which is approximately 1540 meters/second, andthe rate at which digital samples are collected as follows.Distance_per_sample (m)=speed_of_sound (m/s)/samples_per_second(1/s)  Eq. AFor example, if the signal is digitized at 32 million samples persecond, the precision of the measurement due to sampling will be1540/32,000,000=0.048 millimeters.

The timing of the transmit pulse and the collection of data from thereceivers 92 may be synchronized by controller electronics so that thetime of flight can be measured. The receivers 92 can start countingsamples at the same time the transmit burst begins. Each channel willthen continue to count until it detects the arrival of the shortultrasound burst. Although the burst may be many digital samples inlength, a specific sample within the received burst can be chosen as the“official” arrival time in order to achieve maximum accuracy.

There are several possible algorithms that the receivers 92 can employto determine when they have detected the arrival of the ultrasoundpulse. For example, detection of the peak amplitude of the receivedsignal, correlation with the expected pulse shape, or first crossing ofan amplitude above the noise floor could all produce a specific samplenumber that would be used as the detection point for arrival of theburst. While the sampling rate of the received signal may determine theprecision of the measurement, the detection algorithm can influence themeasurement's accuracy.

The size of the volume in which the beacon 36 can be detected willdetermine several design parameters of the system. For example, if thedetection volume is a cylinder whose circular diameter is equal to thediameter of the ring of receivers 92 around the transducer 90 (arepresentative case for vascular sealing) and whose depth is the maximumdepth of the arteriotomy then several parameters can be known. Thesedimensions define the maximum time over which the receiver's TOFdetectors 92 must operate. This volume, along with the attenuation ofthe ultrasound signal in tissue at the chosen frequency will alsodetermine the power required from the beacon and the sensitivityrequired from the receivers 92. For example, if the diameter of the ringof receivers 92 is 45 mm and the maximum depth required is 50 mm thenthe maximum distance from the beacon 36 to the farthest receiver willbe:Sqrt(45²+50 ²)=67.25 mm  Eq. BThe maximum time of flight will be:0.06725 m/1540 m/s=43.67 microseconds

When the time of flight to each receiver 92 is known and the time hasbeen converted to a distance between the beacon 36 and the receiver 92,then the position of the beacon 36 relative to the receivers 92 can becalculated. A minimum of three receivers 92 can be used to calculate theX, Y and Z position of the beacon 36. If more than three sensors areavailable the accuracy of the position calculation can be improved in anumber of ways. For example, if four sensors are available then theposition can be calculated four times with different combinations ofthree sensors and the results could be averaged. Or, if more than threesensors are available, extra weight could be given to those with thebest signal as determined by received amplitude or sharpness of thecorrelation result. These techniques are explained in more detail below.

To calculate the position of the beacon 36, a three dimensionalcoordinate system is defined within the space where the beacon 36 maylie relative to the receivers. In the application with the therapeutictransducer 90, the ring of receivers 92 would conveniently lie in theX,Y plane at the zero crossing of the Z axis (planar constellation ofreceivers 92). The Z axis extends into the body, perpendicular to theface of the transducer 90 and passes through the center of therapy. Thecoordinates of the beacon 36 can be calculated by solving a system ofthree equations with three unknowns. Let x_(i), y_(i) and Z_(i) be thecoordinates of the receivers 92 in the three dimensional coordinatespace where i=1 through 3. Let d_(i) equal the distance from thereceiver 92 to the beacon 36 based on the time of flight measurements.Let X_(b), Y_(b) and Z_(b) be the coordinates of the beacon 36. Then,(X _(b) −x _(i))²+(Y _(b) −y _(i))²+(Z _(b) −z _(i))² =d _(i) ² (for i=1through 3)  Eq. C

There are a number of ways to solve eq. C well know to those skill inthe art. These methods are discussed in greater detail below. Solutionsthat are computationally efficient are preferred, potentially allowinghigher rates of position determinations and/or more computational timefor other system functions.

In some embodiments, sensors, or transducers, for ATOF systems functionwith wide, and to the extent possible, uniform angular sensitivity sothat pulses may be effectively sent and received to and from a varietyof locations in the targeting space. In vascular sealing, where thetransmitting beacon is mounted on a targeting aid positioned in theentry channel, a range of angular orientations with respect to thereceiver constellation results from the fact that entry channels areinclined at various angles to the skin surface. These angles aretypically between 30 and 70 degrees.

For such isotropy, transducers generally can be small with respect tothe dimensions of their acoustic wavelength (e.g., less than one-halfwavelength). Transducers are also preferably dimensionally small so thatthe phase difference (or time delay) across the sensor is small; a largephase difference will distort an accurate time measurement.

Transducer Materials: Materials for ATOF receivers and transmitters maygenerally be any of the materials used in diagnostic imaging. Becauseeither transmit (here in the case of beacons on the targeting aid) orreceive (in the case of the constellation of sensors) is, in many of theembodiments described here, the only function required, materialselection may be optimized for specific transmit or receivecharacteristics.

Materials with various desirable characteristics may include but are notlimited to:

-   -   PZT (lead-zirconate-titanate), readily, economically available        in may forms. Efficient in both transmit and receive.

-   PMN (lead-meta-niobate) similar to PZT

-   PVDF and copolymer film piezo-materials are inexpensive and can be    formed in very small shapes; these are sensitive receivers. When    used as a beacon, they can include sufficeint insulation and    isolation to shield patients from the high voltages used.

-   MEMS transducers (PMUTs and CMUTs) can be attractive because of    their wide bandwidth, and potentially low cost.

-   Barium titanate and other suitable materials.

Transducer Shapes: A variety of transducer shapes may be used. Optimumconfigurations differ generally depending upon whether the transducer ismounted on the targeting catheter or those mounted on the applicator,viz the constellation. For the targeting catheter beacon, cylindricalpiezoceramic elements may be used and offer a number of advantages. FIG.14 depicts use of a cylindrical element having multi-modecharacteristics. A hollow cylindrical transducer 120 has electrodesinside and outside, thus applying a field across the thickness of thecylinder's wall. Several vibrational modes may be selectively driven byselection of drive frequency. Lateral (or radial) mode 122 is the hoopmode; lateral mode 124 is the wall thickness mode; and length mode 126radiates forward as shown. Frequencies and uses of modes are listedbelow for example purposes and are not intended to be limited to:

-   a) Hoop Mode (0.75 MHz):    -   ATOF: Beacon Position Tracking, Station Keeping    -   T/R Doppler: Arteriotomy Position Locating-   b) Wall Thickness Mode (8.5 MHz) (Side View)    -   PW Doppler: Arteriotomy Position Locating    -   T/R Doppler: Arteriotomy Position Locating-   c) Length Mode: (4.0 MHz)    -   PW Doppler: Arteriotomy Position Locating, Station Keeping

Cylindrical transducers may also advantageously be used in multiples,where for example, two transducers are mounted on the distal end of atargeting aid to make up the beacon. More information regarding use oftwo-transducer configurations may be found in U.S. Pat. Nos. 5,515,853;4,407,294; and 4,697,595, all of which are incorporated herein byreference in their entirety.

Spherical or partial-sphere shaped transducers also have advantages ofexcellent isotropy for beacon/TA applications. These transducers alsopresent smooth, rounded surfaces compatible with insertion into thebody. Alternatively, greater isotropy may be realized by operating thetransducers at multiple frequencies where the nulls of the radiationpattern at one frequency are complimented by non-null sensitivity atanother frequency.

For transducers used in the applicator mounted constellation andoperated as receivers, planar structures may provide fabricationadvantages and provide a substantially flat surface that readily couplesto the patient's skin surface. It is noted that, for vascular sealingapplications where the axis of therapy is approximately centered in thetargeting space, high resolution of spatial localization of thetargeting catheter is only needed in the vicinity of the center. Awayfrom the center only rough estimates of targeting catheter are needed inorder to provide the operator directional movement information. FIG. 15depicts one embodiment of an applicator face having ATOF transducerslocated around the periphery, therapeutic transducers located inconcentric circles, and a CW/PW Doppler transducer located at thecenter.

ATOF Distance/Position Computation

Problem: Find the (X, Y, Z) coordinates of a transmitter given thespatial coordinates of N receivers (e.g., N=8) and the distancemeasurements from each one. Let Xi, Yi, Zi be the receiver coordinatesand Di the measured distances, where i=1 . . . N. In the case of aplanar applicator face (see FIG. 15), all Zi are equal, since thereceivers are coplanar. Let Zi=Z₀ for all i.

Solution based on three receivers: A solution for (X, Y, Z) can be foundusing any three receivers, denoted here as 1, 2 and 3. The receivers arecoplanar and arranged in a ring with 45 degree angles between them. Thereceiver closest to the projection of the transmitter onto the receiversplane can be denoted as receiver (1). The other two (2, 3) are thefarthest from the projection, i.e. in an angle of 135 degrees from (1)in both directions. Receiver (1) may have the strongest signal.

The coordinates of the three receivers are: (X₁, Y₁, Z₀), (X₂, Y₂, Z₀)and (X₃, Y₃, Z₀), respectively. The corresponding distance measurementsare D₁, D₂ and D₃. Assuming no error in the measurements, the followingthree equations can be solved for (X, Y, Z):(X−X ₁)²+(Y−Y ₁)²+(Z−Z ₀)² =D ₁ ²(X−X ₂₎ ²+(Y−Y ₂)²+(Z−Z ₀)² =D ₂ ²(X−X ₃)²+(Y−Y ₃)²+(Z−Z ₀)² =D ₃ ²  (1)

These three quadratic equations reduce to two linear equations withunknowns (X, Y) if the first equation is subtracted from the second andthe second from the third. The resulting equations are:2(X ₂ −X ₁)X+2(Y ₂ −Y ₁)=b ₁2(X ₃ −X ₁)X+2(Y ₃ −Y ₁)=b ₂  (2)where,b ₁ =D ₁ ² −D ₂ ² +X ₂ ² +Y ₂ ² −X ₁ ² −Y ₁ ²b ₂ =D ₂ ² −D ₃ ² +X ₃ ² +Y ₃ ² −X ₂ ² −Y ₂ ²

These two equations can easily be solved for (X, Y). Z can then be foundfrom any of the original three equations (a quadratic equation with oneunknown).

Solution based on N receivers: The solution for N receivers involves aniterative minimization process of an objective function that is based onthe sum of square errors from the receivers and can be formulated asfollows:J(X,Y,Z)=Σ(Di−Li)²where is over all receivers i=1 . . . N, Di is the measured distancefrom the transmitter to the i^(th) receiver, and:Li=√(X−X _(i))²+(Y−Y _(i))²+(Z−Z _(i))²is the Euclidian distance from the transmitter location (X, Y, Z) to befound to the i^(th) receiver. Note that no assumptions are made on thecoplanarity of the receivers (i.e. the Z_(i) are not necessarily equal).

Partially differentiating J(X, Y, Z) with respect to X, Y, Z gives thefollowing three equations:∂J/∂X=Σ2(Di−Li)(Xi−X)/Li∂J/∂Y=Σ2(Di−Li)(Yi−Y)/Li∂J/∂Z=Σ2(Di−Li)(Zi−Z)/Li  (3)Equating each of these equations to zero, yields:X=Σ[Xi+Di(X−Xi)/Li]/NY=Σ[Yi+Di(Y−Yi)/Li]/NZ=Σ[Zi+Di(Z−Zi)/Li]/N

The expressions (X−Xi)/Li, (Y−Yi)/Li and (Z−Zi)/Li are the cosine of theangles between the transmitter and i^(th) receiver and its projectioninto the Y-Z, X-Z and Y-Z planes respectively. Therefore, the aboveequations can be written as:X=Σ[Xi+Di Cos(θ_(YZ))]/NY=Σ[Yi+Di Cos(θ_(XZ))]/NZ=Σ[Zi+Di Cos(θ_(YZ))]/N  (4)

The angles depend on the transmitter location (X, Y, Z). However, to agood approximation, it can be assumed that these angles will not vary bymuch between iterations. Therefore the angles from the (k−1)^(th)iteration can be used in the k^(th) iteration.

The algorithm can be stated as follows:

-   1. Choose initial conditions for the transmitter location (X, Y, Z).    This can be done using any three receivers, for example as shown in    Part 1.-   2. Calculate initial Li, i=1 . . . N and the initial objective    function J(X, Y, Z).-   3. Repeat K times with iteration counter k=1 . . . K:    -   a. Calculate Li, i=1 . . . N and the objective function J(X, Y,        Z)    -   b. If the absolute value of the difference between J in the        (k−1)^(th) iteration and the k^(th) (current) iteration is less        than ε, stop.    -   c. Calculate the cosine angles Cos(θ_(YZ)), Cos(θ_(XZ)) and        Cos(θ_(YZ)) based on the last iteration.    -   d. Update the transmitter location (X, Y, Z) based on equations        (4).-   4. End iteration loop.

Returning to the discussion of the flow chart in FIG. 5, at block 108,after aligning the applicator using the beacon, the user may applyadditional hemostatic compression with the applicator so as totransiently either partially or fully occlude the artery. By temporarilyreducing or completely stopping blood flow, less energy required to bedelivered at the arteriotomy to perform thermal hemostasis, since vesselblood flow serves to dissipate focused delivery of energy. Duringcompression, care may be taken to maintain accurate targeting.

The use of additional transducers and sensors may be used to aid incompression measurement feedback to the user. An example of suchtransducers and sensors may include a Doppler transducer and a forcesensor, each located in the applicator, to continuously interrogate thevascular blood flow and the applied compressive force, respectively. Acompression algorithm resident in the generator may be used to analyzesignals from the sensors and produce graphical feedback on theapplicator display to enable the user to apply and maintain adequatecompression of the arteriotomy (see compression indicator in FIG. 12).Alternatively or in addition to these sensors, a sensor capable ofmonitoring blood flow and artery pressure properties may be located onthe targeting catheter. Non-limiting examples of such a sensor includeDoppler ultrasound sensors, an optical fiber sensor, thermal sensors, orother pressure/flow sensors used to monitor blood flow characteristics.Pressure sensors attached to the therapeutic transducer can becalibrated with respect to the blood flow sensors located in the arteryon the targeting catheter. Upon removal of the targeting catheter, thepressure sensors located on the therapeutic applicator can be used todetermine the status of the vessel (e.g. unobstructed, partiallyoccluded, or fully occluded). Additionally, external blood flow/pressuresensors may also be used such as traditional manual stethoscope incombination with the application of pressure

FIG. 7E illustrates the applicator 20 applying force against the tissue31 causing the vessel 28 to transiently be either partially or fullyoccluded. The reasons for applying pressure are to stop the bleedingoccurring at the wall puncture site prior to (as described above) andduring the application therapeutic energy dose. Additionally, byreducing or eliminating blood flow through the vessel 28, efficientdelivery of thermal energy to cause hemostasis is promoted, since vesselblood flow serves to dissipate the delivered thermal energy.

It is has been discovered that one can improve the efficiency of thermalenergy vascular closure by administering the thermal energy (e.g. highintensity focused ultrasound) under conditions whereby all tissue bloodflow related convective cooling can be eliminated; specifically bleedingwhich occurs in the introducer track and from the arterial (luminal)blood flow. Accordingly, one embodiment involves applying thetherapeutic applicator with pressure of sufficient magnitude to causethe artery to be temporarily occluded during the dose (power-on) periodof the thermal energy and perhaps continuing for a short period duringall, or a portion of, the post-dose compression period. This treatmentcondition is termed “transient arterial occlusion” (TAO).

The following experiments were undertaken in order to demonstrate thatthe delivery of thermal dose in combination with TAO surprisingly didnot adversely cause the lumen to be permanently occluded (e.g. theinterior walls of the artery to be welded shut). FIG. 50 illustrates atesting device used to evaluate if thermal energy in combination withTAO causes the intimal walls of the artery to weld together. FIG. 50illustrates bovine carotid 550 with a needle puncture arteriotomypressed between two aluminum plates 555. The plates are compressedtogether using spring clamps 560 and aligned with alignment pins 570.Compression force was measured at 25 lbs. A thermocouple 565 was locatedwithin the transiently occluded bovine artery. This test apparatus wasthen fully submerged in boiling saline for 1 minute. The temperature andtime were chosen to exceed the temperature and equal the time exposurethat occurs during one embodiment of delivering high intensity focusedultrasound for arterial hemostasis (e.g., 70° C. and 40 seconds,respectively). FIG. 51 is a photograph of the bovine carotid sandwichedbetween the two aluminum plates after a 60 second submersion in boilingsaline.

FIG. 52 is a graph of the measured temperature from the thermocouplelocated within the TAO during the time in which the apparatus wassubmerged in boiling saline. The temperature of the bovine arteryreached 70° C. (a targeted temperature at which the native perivascularcollagen is denaturaized and forms an extensive fibrin network thatcovers the arteriotomy) within 11 seconds and then equilibrates to 100°C. within 40 seconds. The temperature of the boiling saline bath wasmeasured but remained constant at 100° C. Upon removal of the apparatusfrom the boiling saline, the spring clamps and aluminum plates wereremoved and the artery was cut in order to inspect the lumen to observeif any portion of the intimal surface was welded together. Asillustrated in FIG. 53 the artery springs opened after being cutindicating that there was no occurrence of tissue welding during TAO andthermal dosing. Lastly, the bovine artery was pressure tested toevaluate the strength of the sealed arteriotomy. The artery wassubmerged in room temperature saline and fully pressurized with air andthe pressure was recorded while being increased until the air leakedthrough the arteriotomy. Table 3 illustrates the results of thedestructive sealed arteriotomy pressure testing. Over seven experiments,the intimal surface of the arteries did not weld shut and thearteriotomy was sealed and successfully pressure tested up to at least 3psi. TABLE 3 Pressure and welding testing of bovine arteries under TAO.Pressure resistance Time occluded Artery Welded? of arteriotomy sealabove 70° C. 1 No 3 psi (155 mmHg) 49 sec 2 No >4 psi (207 mmHg) 46 sec3 No >4 psi (207 mmHg) 50 sec 1 No 3.3 psi (171 mmHg) 47 sec 2 No >5 psi(259 mmHg) 53 sec 3 No >4 psi (207 mmHg) 49 sec 4 No >5 psi (259 mmHg)49 sec

By monitoring the blood flow levels in the artery 28 while measuring theapplied pressure, one can determine the optimal applied pressure andthereby maintain this pressure throughout the procedure. FIG. 12 is anillustration of one possible user interface that displays the amount oftherapeutic applicator compression 120 applied by the user. The desplaymay be coupled to the blood flow sensor to provide an indication ofblood flow and hence compression. This user interface may be continuallyviewed by the user to insure proper compression is applied by thetherapeutic applicator.

In one embodiment, the pressure sensing capability of piezoelectricmaterial in the ultrasound transducers located on the applicator may beused to monitor the presure applied by the applicator. This method givesa direct measurement of the pressure at the surface of the applicator.This pressure can be correlated with typical pressures required to stoppuncture track blood flow, maintain artery patency, partially occludethe artery, or fully occlude the artery. In other embodiments describedabove, the pressure may be monitored by sensors located on a targetingcatheter (e.g., piezoelectric sensors that measure blood flow usingDoppler effects).

The amount of pressure at the surface of the applicator transducers canbe detected using impedance changes within the piezoelectric elements ora change in voltage at the element. This technique allows detection ofpressure directly at the applicator face. In addition, uneven pressuremay be detected by separately making measurements from multiple elementsat different spatial locations. By using the existing piezoelectricelements in the therapeutic ultrasound array, no additional materialsneed to be added. Pressure at the surface of the applicator can becorrelated to the occlusion status of the vessel and to the compressionrequired to stop blood flow up the introducer track. The existingcapability in the generator may be used to monitor power, voltage,current and phase.

Piezoelectricity is a property of certain classes of crystallinematerials including natural crystals of Quartz, Rochelle Salt andTourmaline as well as manufactured ceramics or polymer films such asLead Zirconate Titanates (PZT) and polyvinylidene fluoride. When anelectric field is applied to the materials, the material deformsdepending on the orientation. Conversely, when a stress is applied, anelectric field is produced in the material.

In one embodiment, the applicator design uses PZT to produce anultrasound wave when excited electrically. Since PZT is a syntheticcrystal structure, the material is naturally isotropic and thereforenon-piezoelectric. PZT must go through a poling process where a highvoltage is applied at elevated temperatures to orient the net effect ofthe material domains in one direction. During the poling process, thematerial expands in the direction of the electric field.

After the PZT has been poled, expansion or contraction of the materialwill create a build-up of charge at the poling electrodes. If thecompression force is in the poling direction, then the voltage polaritydetected is the same as the poling voltage. If a tensile force isapplied, then the voltage polarity detected is the opposite of thepoling voltage.

This piezoelectric effect can be used to detect the amount of pressureat the surface of the transducer. The magnitude of the voltage isrelated to the receiving constant (g) of the piezoelectric material aswell as the magnitude of the stress applied (T) and thickness of theceramic (t).V _(oc) =g*T*t  (eq. 8)where V_(oc) is the open circuit voltage received at the element.Therefore, if a resistive load is connected to the terminals of thedevice, the charge created would be electrically dissipated. The shapeof the signal at the piezoelectric element is dependent on the impulseof the stress and the time constant with the load. The amount of chargeon the device is dependent on the voltage and element capacitance.

In order to test the significance of this effect, an Antares VF10-5transducer (Siemens A G, Munich, Germany), 10× probe, and oscilloscopewas used to detect the voltage produced by a stress. One element in theVF10-5 transducer was connected to the 10× probe. The 10× probe wasconnected to a Tektronix oscilloscope (Tektronix, Inc., Beaverton, OR)that was set for a single shot trigger. The transducer face was thenpressed onto a hard surface and released. Similarly, the transducer facewas pressed with a thumb and released. FIGS. 16 and 17 show themagnitude of the voltage detected. Since the charge on the transducerelement is being dissipated through the 10× probe, the shorter theimpulse, the larger the voltage signal detected. Overall, voltages above20 mV were detected in this experiment (FIGS. 16 and 17). This issignificant given the overall small element size (approximately 150 umwide by 5 mm tall) and long coaxial cable (2.1 m) between the elementand 10× probe.

Although the experiment with the VF10-5 showed that pressure changeswere detectable, the magnitude detected is dependent on impulse signalcreated by the impulsive load delivered.

Next, an experiment was conducted to detect the impedance of thetherapeutic elements with and without a pressure at the face. Atherapeutic applicator was placed in a water bath and a low voltage (3V) CW signal at 2 MHz from the generator excited the elements of thetransducer. The power, voltage, current and phase were monitored. Next,pressure was applied to the face of the transducer and the variableswere again monitored. Phase changes on the order of 10 degrees weredetected when the pressure was applied. Since the current and voltagewaveforms were more in-phase with the application of a compressivestress, the power increased. A force balance can be applied to determinethe relationship between pressure magnitude and amount of phase change.

Another means to monitor the status of the a vessel (open, partiallyoccluded or fully occluded) is to use an acoustic Doppler system placedonto the patients skin to analyze vessel wall Doppler sounds to providean indication of “proper” compression levels and on-location feedback.This measurement is useful since the compression of the artery willaffect the Doppler sounds obtained from a transducer that is mountedperpendicular to the flow even though there is no flow signal.Turbulence and wall motion will be present which will yield differentDoppler signals than when the arteries is either fully open or fullycollapsed.

Returning to the discussion of the flowchart in FIG. 5, at block 110,after the desired level of compression is applied, a station keepingmethod can be initiated to maintain proper alignment of the applicatorduring therapy. Subsequent to alignment, the targeting cathetercontinues to reside in the puncture tract with the beacon beingproximate to the arteriotomy. The application of therapeutic energy maybe applied at this point, however, in some embodiments, the procedureinvolves removing the targeting catheter from the arteriotomy location(discussed in more detail below). Removing the targeting catheter allowsfor the most effective acoustic hemostasis. In some embodiments, methodsare provided to ensure that the therapeutic applicator stays focusedupon the arteriotomy in the absence of the beacon. In anticipation ofthe targeting catheter being removed, a station keeping method may beinitiated as illustrated in FIG. 7F. Station keeping, which is describedin detail below, may be used to track tissue 31 motion (e.g.,specifically the arteriotomy 30 or tissue proximate to it) usingacoustic waves with radio frequency signal processing techniques(referred to herein as RfUME (Radio Frequency Ultrasound MotionEstimate)). Specifically, at least three acoustic transducers, pistons,or arrays may be used to track the motion of a common point. Movementmay be determined by comparing a reference signal to a present signal.The difference between the signals determines the amount of movement ofthe tissue 31 relative to the transducers and hence relative to theapplicator 20.

Accordingly, in anticipation of removing the targeting catheter 32, theATOF targeting of the arteriotomy targeting aid 34 and beacon 36 may bereplaced by station keeping of the arteriotomy site 30. This stationkeeping information may be displayed to the user through the sametargeting user interface as depicted in FIG. 12. This display providesfeedback to a user so that the user can maintain the focus point of thetherapeutic energy applicator 20 at the site of the arteriotomy 30.

The purpose of station keeping is to track tissue motion. In oneembodiment, at least three transducers may be used to track the motionof a common point. The motion may be tracked using a variety oftechniques including traditional pulse-echo techniques as well as apitch-catch sequence. The pitch-catch algorithm has several advantageswhen compared with conventional pulse-echo techniques. The acquisitiontime required to determine the motion is significantly reduced, therebyreducing the susceptibility to jitter, allowing the system to see fastermovements, and allowing more time for therapy if interleaving is used.In addition, a greater amount of redundancy is achieved in lessacquisition time for improved motion estimation. If the pitch-catchtechnique is allocated the same acquisition time as the conventionalapproach, the SNR of each acquisition is also increased, therebyincreasing penetration and improving tracking ability. Finally, systemcomplexity is reduced by reducing hardware requirements (e.g.transmit-receive switches).

The overlapping beam pattern of at least three ultrasound transducerscan be used to track the motion in three dimensions. In this case, aunit vector from the transducer to the coordinate system of theinterrogated point describes the beam direction and sensitivity tospecific types of movement. If the interrogated point moves relative tothe transducer, then a certain amount of movement will be detected byeach transducer depending on the unit vector. In this case, the amountof motion detected at one transducer is described as:motion_(k) =a _(kx) ·δx +a _(ky) ·δy+a _(kz) ·δz  (9)where δ_(x), δ_(y), and δ_(z) are the small movements of the point fromthe original position in three dimensions, and a_(kx), a_(ky), anda_(kz) are the unit vector components for the k^(th) transducer. Theamount of motion can be calculated by measuring the amount of movementfrom at least two other transducers and realizing that the motiondetected in ultrasound is related to a time shift: $\begin{matrix}{{motion}_{k} - {t_{k} \cdot \frac{c_{tissue}}{2}}} & (10)\end{matrix}$where t_(k) is the time difference between the first signal and the nextsignal, and c_(tissue) is the velocity of sound in tissue. The factor oftwo occurs in equation (10) due to the time required for the ultrasoundpulse to travel out and back from the interrogation point. The timedifference t_(k) is determined by fitting a previous or reference pulseto the current pulse. A correlation technique is typically used todetermine the best fit. Therefore, the system can be described bycombining equations (9) and (10) to obtain: $\begin{matrix}{\begin{bmatrix}t_{1} \\t_{2} \\t_{3}\end{bmatrix} = {\frac{2}{c_{tissue}} \cdot \begin{bmatrix}a_{1x} & a_{1y} & a_{1z} \\a_{2x} & a_{2y} & a_{2z} \\a_{3x} & a_{3y} & a_{3z}\end{bmatrix} \cdot \begin{bmatrix}{\delta\quad x} \\{\delta\quad y} \\{\delta\quad z}\end{bmatrix}}} & (11)\end{matrix}$

If the time differences are known as well as the unit vectors given thesystem configuration, then the amount of motion can be determined. Ifthe system has multiple transducers, then redundancy exists in thesystem and multiple solutions can be calculated.

In the pitch-catch approach, instead of transmitting and receiving onthe same transducer, energy is transmitted by only one transducer andthe backscatter is detected by the other transducers. For example, if athree transducer system is used, the transmit event might occur ontransducer 1 with transducer 2 and 3 detecting the backscatter. A secondtransmit might occur on transducer 2 with transducer 1 and 3 detectingthe backscatter. In this case, the motion detected is a combination ofthe unit vectors from the transmit and receive transducers.motion_(k)=(a _(kx) +a _(mx))·δx+(a _(ky) +a _(my))·δy+(a _(kz) +a_(mz))·δz  (12)where the directional vector is the summation of the unit vectorcomponents for the k_(th) and m_(th) transducers. Another interestingresult of equation 12 is the lack of identification of the transmit andreceive transducers. In other words, reciprocity exists in equation(12). The k_(th) transducer could either be the transmitter or receiverand the motion detected is the same amount.

Similar to the conventional pulse-echo approach, the amount of motiondetected is related to the time shift in the receive pulse. However, inthis case the factor of two is eliminated because the pulse is not goingout and coming back; rather it is detected by the path between thetransmitter and receiver which is already represented in the directionalvector.motion_(k)=t_(k)·C_(issue)  (13)

Equations (12) and (13) can be combined to show the relationship betweenthe time shift and the motion of the interrogation point.$\begin{matrix}{\begin{bmatrix}t_{1} \\t_{2} \\t_{3}\end{bmatrix} = {\frac{1}{c_{tissue}} \cdot \begin{bmatrix}\left( {a_{1x} + a_{2x}} \right) & \left( {a_{1y} + a_{2y}} \right) & \left( {a_{1z} + a_{2z}} \right) \\\left( {a_{1x} + a_{3x}} \right) & \left( {a_{1y} + a_{3y}} \right) & \left( {a_{1z} + a_{3z}} \right) \\\left( {a_{2x} + a_{3x}} \right) & \left( {a_{2y} + a_{3y}} \right) & \left( {a_{2z} + a_{3z}} \right)\end{bmatrix} \cdot \begin{bmatrix}{\delta\quad x} \\{\delta\quad y} \\{\delta\quad z}\end{bmatrix}}} & (14)\end{matrix}$

In this case, the transmit might occur on transducer 1 and detection ontransducers 2 and 3. This would yield t₁, and t₂. A second transmitmight occur on transducer 2 and detection could occur on transducer 1and 3. In this case, t₁, and t₃ are determined; however, note that onlyt₃ is required to allow for equation (14) to be solved for the movement.The extra t₁ measured time could be used to improve the estimate (SNR)or just discarded.

Compared to the conventional approach, only two transmit events arerequired to solve for the movement in equation 14. Therefore, the amountof time to acquire and calculate a movement has decreased by 33%. Thisextra time can be used to increase the acquisition rate and detectfaster movements. This extra time may also be dedicated for therapy.

The pitch-catch method also has the advantage for reducing the hardwarerequired. For example, in the three transducer system, two transducersrequire a transmit/receive architecture with the other transducer onlyrequiring a receive architecture. In the conventional case, all threetransducers need a transmit/receive architecture.

In the case of more than three transducers, the pitch-catch approachoffers the possibilities of motion estimation redundancy with only onetransmit. For example, if the system has five transducers, thentransmitting on one transducer yields the possibility of four differentsolutions. This redundancy allows for better motion estimation throughaveraging techniques or solution selection given the signal quality. Inthe conventional approach, at least four transmit events are requiredfor this amount of redundancy in a five transducer system.

In some embodiments, the pulse-echo and pitch-catch approach may becombined in a hybrid approach to yield an even faster acquisition. Inthis case, equation (14) becomes: $\begin{matrix}{\begin{bmatrix}t_{1} \\t_{2} \\\frac{t_{3}}{2}\end{bmatrix} = {\frac{1}{c_{tissue}} \cdot \begin{bmatrix}\left( {a_{1x} + a_{2x}} \right) & \left( {a_{1y} + a_{2y}} \right) & \left( {a_{1z} + a_{2z}} \right) \\\left( {a_{1x} + a_{3x}} \right) & \left( {a_{1y} + a_{3y}} \right) & \left( {a_{1z} + a_{3z}} \right) \\\left( a_{1x} \right) & \left( a_{1y} \right) & \left( a_{1z} \right)\end{bmatrix} \cdot \begin{bmatrix}{\delta\quad x} \\{\delta\quad y} \\{\delta\quad z}\end{bmatrix}}} & (15)\end{matrix}$

In this case, the system has transmitted on transducer 1 and received onall three transducers. Acquisition time is decreased by 67% whencompared to the conventional approach with three transducers.

In order to evaluate the performance of the pitch-catch technique, afixture with three 6 mm ultrasonic pistons was design and tested. Thefixture was coupled to an agar phantom and pitch-catch data was acquiredand motion estimation was calculated off-line. A Panametrics 5072PRpulser was used as the transmitter and a Metrotek MR101 receiver wasused. FIGS. 18, 19 and 20 are graphs showing the correlation betweenactual position and that determined using the pitch-catch RfUMEalgorithm described above for X, Y, and Z coordinates, respectively. Theideal result of one-to-one correlation is plotted as a line of slope 1.The distances determined using the RfUME algorithm are plotted ascircles. FIGS. 18, 19 and 20 show that after a certain amount ofmovement, the algorithm stops tracking. This result is primarily due tothe beam width and the transducer directionality. For example,improvement in tracking x and y movement can be accomplished by wideningthe beam or placing the transducer at a steeper interrogation angle suchthat the transducer has greater detection of x and y movement. Althoughthe algorithm stops tracking after a certain amount of movement, thiseffect can be avoided in real-time by referencing when required.

As discussed above, movement relative to tissue is determined bycomparing a reference signal to a present signal. The phase differencebetween these signals helps determine the amount of movement of thetransducer or tissue. Unfortunately, this motion estimation is asimplification of the actual movement. Accordingly, such algorithms havethe potential of significant error if the transducer or tissue moves bylarge amounts or if the transducer is tipped or tilted. Thus, in someembodiments, a recursive algorithm is used to determine the movement.Results show that the recursive algorithm tracks movement due torotation much better than the simplified version. The error fortranslational movement is also reduced from approximately 5% to lessthan 2%. There are several benefits of using the recursive algorithmapproach. The motion estimation due to elevation or roll rotation issignificantly improved, especially in the depth dimension. In addition,the standard deviation of the motion estimation is reduced fromapproximately 5% to less than 2%. No simplification of the acousticformulas is required to track movement. Furthermore, only a small amountof iterations are required for the system to reach equilibrium

In some embodiments, a conventional pulse-echo approach may be utilizedfor station keeping. The overlapping beam pattern of at least threetransducers can be used to track the motion in three dimensions. In thiscase, a unit vector from the transducer to the coordinate system of theinterrogated point describes the beam direction and sensitivity tospecific types of movement. If an interrogated point moves relative tothe transducer, then a certain amount of movement will be detected byeach transducer depending on the unit vector. In this case, the amountof motion detected at one transducer is described as:motion_(k) =a _(kx) ·Δx+a _(ky) ·Δy+a _(kz) ·ΔZ  (16)where δx, δy, and δz are the small movements of the point from theoriginal position in three dimensions, and a_(kx), a_(ky), and a_(kz)are the unit vector components for the k^(th) transducer. The amount ofmotion can be calculated by measuring the amount of movement from atleast two other transducers and realizing that the motion detected inultrasound is related to a time shift: $\begin{matrix}{{motion}_{k} - {t_{k} \cdot \frac{c_{tissue}}{2}}} & (17)\end{matrix}$where t_(k) is the time difference between the first signal and the nextsignal, and c_(tissue) is the velocity of sound in tissue. The factor oftwo occurs in equation (17) due to the time required for the ultrasoundpulse to travel out and back from the interrogation point. The timedifference t_(k) is determined by fitting a previous or reference pulseto the current pulse. A correlation technique is typically used todetermine the best fit. Therefore, the system can be described bycombining equations (16) and (17) to obtain: $\begin{matrix}{\begin{bmatrix}t_{1} \\t_{2} \\t_{3}\end{bmatrix} = {\frac{2}{c_{tissue}} \cdot \begin{bmatrix}a_{1x} & a_{1y} & a_{1z} \\a_{2x} & a_{2y} & a_{2z} \\a_{3x} & a_{3y} & a_{3z}\end{bmatrix} \cdot \begin{bmatrix}{\Delta\quad x} \\{\Delta\quad y} \\{\Delta\quad z}\end{bmatrix}}} & (18)\end{matrix}$

If the time differences are known as well as the unit vectors given thesystem configuration, then the amount of motion can be determined. Ifthe system has multiple transducers, then redundancy exists in thesystem and multiple solutions can be calculated.

A recursive approach may also be used with convention pulse-echotechniques. In the recursive approach, instead of assuming that the unitvector from the center of the transducer to the interrogation pointcompletely maps the movement, a new approach is formulated using thedistance formula. For example, assume that the transducers are in thesame plane a distance ‘R’ from the center of a circle. In this case, theoriginal distance to a common interrogation point is: $\begin{matrix}{d_{io} = \sqrt{\left( {R \cdot {\cos\left( {\frac{2 \cdot \pi}{N} \cdot \left( {i - 1} \right)} \right)}} \right)^{2} + \left( {R \cdot {\cos\begin{pmatrix}{\frac{2 \cdot \pi}{N} \cdot} \\\left( {i - 1} \right)\end{pmatrix}}} \right)^{2} + z_{f}^{2}}} & (19)\end{matrix}$where R is the distance from the center of the circle to the center ofeach transducer, N is the number of transducers which is greater than orequal to three, i varies from 1 to N, and Z_(f) is the distance to theinterrogation point. In this case, the interrogation point is only onthe z axis. Equation (19) simplifies to:d _(io) =√ R²+z_(f) ²   (20)This results makes sense for this system design, given that eachtransducer is equidistant from the interrogation point.

If the target moves to a new point described as (Δx, Δy, z_(f)+Δz),where the movement can be caused by tissue movement or transducermovement, the new distance to the target is given as: $\begin{matrix}{d_{in} = \sqrt{\begin{matrix}\begin{matrix}{\left( {{R \cdot {\cos\left( {\frac{2 \cdot \pi}{N} \cdot \left( {i - 1} \right)} \right)}} + {\Delta\quad x}} \right)^{2} +} \\{\left( {{R \cdot {\sin\left( {\frac{2 \cdot \pi}{N} \cdot \left( {i - 1} \right)} \right)}} + {\Delta\quad y}} \right)^{2} +}\end{matrix} \\\left( {z_{f} + {\Delta\quad z}} \right)^{2}\end{matrix}}} & (21)\end{matrix}$

In the technique to determine motion, the phase difference of areference line to a current line is determined. This technique issimilar to calculating the difference between the distance vectors.V _(in) =d _(in) −d _(io)  (22)where v_(in) is the difference between the two distances for transducer‘i’. Unfortunately, it is difficult to solve equation (22) for Δx, Δy,and Δz because of the square root. Therefore, it may be possible tocalculate the movement if equations (20) and (21) are first squared.$\begin{matrix}{{d_{in}^{2} - d_{io}^{2}} = {\left( {{R \cdot {\cos\left( {\frac{2 \cdot \pi}{N} \cdot \left( {i - 1} \right)} \right)}} + {\Delta\quad x}} \right)^{2} + \left( {{R \cdot {\sin\left( {\frac{2 \cdot \pi}{N} \cdot \left( {i - 1} \right)} \right)}} + {\Delta\quad y}} \right)^{2} + \left( {z_{f} + {\Delta\quad z}} \right)^{2} - \left( {R^{2} + z_{f}^{2}} \right)}} & (23)\end{matrix}$Simplifying equation (23) yields: $\begin{matrix}{\frac{d_{in}^{2} - d_{io}^{2} - \left( {{\Delta^{2}x} + {\Delta^{2}y} + {\Delta^{2}z}} \right)}{2} = {{{R \cdot {\cos\left( \theta_{i} \right)} \cdot \Delta}\quad x} + {{R \cdot {\sin\left( \theta_{i} \right)} \cdot \Delta}\quad y} + {{z_{f} \cdot \Delta}\quad z\quad{where}\quad\theta_{i}\quad{is}\quad 2{\pi/{{N\left( {i - 1} \right)}.}}}}} & (24)\end{matrix}$If both sides of equation (24) are divided by equation (20), then:$\begin{matrix}{\frac{d_{in}^{2} - d_{io}^{2} - \left( {{\Delta^{2}x} + {\Delta^{2}y} + {\Delta^{2}z}} \right)}{2 \cdot \sqrt{R^{2} + z_{f}^{2}}} = {{{a_{ix} \cdot \Delta}\quad x} + {{a_{iy} \cdot \Delta}\quad y} + {{a_{iz} \cdot \Delta}\quad z}}} & (25)\end{matrix}$where a_(ix), a_(iy), and a_(iz), are the x, y and z unit vectors fromtransducer ‘i’.

In practice, the actual distances are not calculated from the signalvectors, rather the time differences between the pulses are calculated.A distance can be related to time by knowing the speed of sound.$\begin{matrix}{t_{i} = \frac{d_{i}}{\left( \frac{c_{tissue}}{2} \right)}} & (26)\end{matrix}$If equation (26) is substituted into equation (25), then:$\begin{matrix}\begin{matrix}{{\left( \frac{c_{tissue}}{2} \right)^{2} \cdot \left( \frac{t_{in}^{2} - t_{io}^{2} - {\frac{4}{c_{tissue}^{2}}\left( {{\Delta^{2}x} + {\Delta^{2}y} + {\Delta^{2}z}} \right)}}{2 \cdot \sqrt{R^{2} + z_{f}^{2}}} \right)} =} \\{{{a_{ix} \cdot \Delta}\quad x} + {{a_{iy} \cdot \Delta}\quad y} + {{a_{iz} \cdot \Delta}\quad z}}\end{matrix} & (27)\end{matrix}$Equation (27) can now be placed into matrix form for a three transducersystem: $\begin{matrix}\begin{matrix}{{\frac{c_{tissue}^{2}}{8 \cdot \sqrt{R^{2} + z_{f}^{2}}} \cdot \begin{bmatrix}{t_{1n}^{2} - t_{1o}^{2} - {\frac{4}{c_{tissue}^{2}}\left( {{\Delta^{2}x} + {\Delta^{2}y} + {\Delta^{2}z}} \right)}} \\{t_{2n}^{2} - t_{2o}^{2} - {\frac{4}{c_{tissue}^{2}}\left( {{\Delta^{2}x} + {\Delta^{2}y} + {\Delta^{2}z}} \right)}} \\{t_{3n}^{2} - t_{3o}^{2} - {\frac{4}{c_{tissue}^{2}}\left( {{\Delta^{2}x} + {\Delta^{2}y} + {\Delta^{2}z}} \right)}}\end{bmatrix}} =} \\{\begin{bmatrix}a_{1\quad x} & a_{1\quad y} & a_{1\quad z} \\a_{2\quad x} & a_{2\quad y} & a_{2\quad z} \\a_{3x} & a_{3\quad y} & a_{3z}\end{bmatrix} \cdot \begin{bmatrix}{\Delta\quad x} \\{\Delta\quad y} \\{\Delta\quad z}\end{bmatrix}}\end{matrix} & (28)\end{matrix}$

A recursive formula is generated by solving equation (28) for Δx, Δy,and Δz. In this case, the calculated motion is still a function of thedistance squared. Therefore, in order to get an initial estimate of themovement, assume that the time differences are much larger than the sumof the square of the movement divided by the speed of sound in tissue.In this case, the solution is: $\begin{matrix}\begin{matrix}{{\frac{c_{tissue}^{2}}{8 \cdot \sqrt{R^{2} + z_{f}^{2}}} \cdot \begin{bmatrix}a_{1\quad x} & a_{1\quad y} & a_{1\quad z} \\a_{2\quad x} & a_{2\quad y} & a_{2\quad z} \\a_{3x} & a_{3\quad y} & a_{3z}\end{bmatrix}^{- 1} \cdot \begin{bmatrix}{t_{1n}^{2} - t_{1o}^{2}} \\{t_{2n}^{2} - t_{2o}^{2}} \\{t_{3n}^{2} - t_{3o}^{2}}\end{bmatrix}} =} \\{\begin{bmatrix}1 & 0 & 0 \\0 & 1 & 0 \\0 & 0 & 1\end{bmatrix} \cdot \begin{bmatrix}{\Delta\quad x} \\{\Delta\quad y} \\{\Delta\quad z}\end{bmatrix}}\end{matrix} & (29)\end{matrix}$Also note that: $\begin{matrix}{t_{i\quad 0}^{2} = {\left( \frac{2}{c_{tissue}} \right)^{2} \cdot \left( {R^{2} + z_{f}^{2}} \right)}} & (30)\end{matrix}$This result is the initial calculation of the movement and the estimatesfor Δx, Δy, and Δz can be placed in the left side of the equation, andthe motion calculated again according to equation (31). $\begin{matrix}{{\frac{c_{tissue}^{2}}{8 \cdot \sqrt{R^{2} + z_{f}^{2}}} \cdot \begin{bmatrix}a_{1\quad x} & a_{1\quad y} & a_{1\quad z} \\a_{2\quad x} & a_{2\quad y} & a_{2\quad z} \\a_{3x} & a_{3\quad y} & a_{3z}\end{bmatrix}^{- 1} \cdot \begin{matrix}{\begin{bmatrix}{t_{1n}^{2} - t_{1o}^{2} - {\frac{4}{c_{tissue}^{2}}\left( {{\Delta^{2}x_{m - 1}} + {\Delta^{2}y_{m - 1}} + {\Delta^{2}z_{m - 1}}} \right)}} \\{t_{2n}^{2} - t_{2o}^{2} - {\frac{4}{c_{tissue}^{2}}\left( {{\Delta^{2}x_{m - 1}} + {\Delta^{2}y_{m - 1}} + {\Delta^{2}z_{m - 1}}} \right)}} \\{t_{3n}^{2} - t_{3o}^{2} - {\frac{4}{c_{tissue}^{2}}\left( {{\Delta^{2}x_{m - 1}} + {\Delta^{2}y_{m - 1}} + {\Delta^{2}z_{m - 1}}} \right)}}\end{bmatrix} =}\end{matrix}}\begin{matrix}{\begin{bmatrix}1 & 0 & 0 \\0 & 1 & 0 \\0 & 0 & 1\end{bmatrix} \cdot \begin{bmatrix}{\Delta\quad x_{\quad m}} \\{\Delta\quad y_{\quad m}} \\{\Delta\quad z_{\quad m}}\end{bmatrix}}\end{matrix}} & (31)\end{matrix}$In this case, the index m denotes the number of times through thecalculation.

In order to determine the advantages using the recursive formulation,data was simulated using the Field II program by Jorgen Jensen. Thisallowed a phantom of random scatterers to be easily rotated in elevationand roll. A 16 element phased array operating at 2 MHz with 60%bandwidth was defined in Field II and placed uniformly around a radiusof 12.5 mm. The conventional algorithm was applied to the data todetermine the calculated x, y and z motion. For example, since elevationrotation is about the x-axis, movement is expected in the y and zdimensions. The recursive formula was also applied to the exact samedata and a comparison was made to actual movement in x, y and z.

FIG. 21 depicts three graphs showing the actual movement (plottedcircles) in x, y and z, respectively, compared to the line representingthe calculated result using the conventional technique (eq. 18) forrotation in elevation. In this case, the three phased arrays are focusedat a 50 mm depth. Although this algorithm detects the y movement andlack of x movement with a high degree of accuracy, no movement isdetected in the z dimension. A similar result is observed for rollrotation (see FIG. 22).

FIG. 23 shows the results using the recursive formula (eq. 31) forelevation rotation. In this case, the algorithm detects accurately themotion in all three dimensions. This result only required 10 iterationsof the formula (m=10). A similar result is observed for roll rotation(see FIG. 24).

A calibration process may be used to calibrate an ultrasound system usedto track tissue motion. The direction of the ultrasound propagation tothe focus is directly related to the amount of detected movement.Therefore, it is advantageous to know the direction vector from thetransducers to the focus with a high degree of accuracy. Any errors havethe potential to be compounded if re-referencing frequently.Re-referencing may be required due to the limited region that thetransducers can detect movement. The following discussion describes aprocess to calibrate the direction of ultrasound propagation from a setof transducer, pistons or arrays. The process provides a significantreduction in potential errors resulting in improved accuracy of motionestimation with significantly reduced error for pistons or multi-elementarrays, increased mechanical alignment tolerances since acousticcalibration eliminates these errors, and reduction in susceptibility toaccumulation error.

The overlapping beam pattern of at least three transducers can be usedto track the motion in three dimensions. In this case, a unit vectorfrom the transducer to the coordinate system of the interrogated pointdescribes the beam direction and sensitivity to specific types ofmovement. If the interrogated point moves relative to the transducer,then a certain amount of movement will be detected by each transducerdepending on the unit vector. In this case, the difference in the squareof distance vectors is described as: $\begin{matrix}\begin{matrix}{{d_{i\quad n}^{2} - d_{io}^{2}} = {\left( {{{R \cdot \cos}\left( \quad{\frac{2 \cdot \pi}{\quad N} \cdot \left( {i\quad - \quad 1} \right)} \right)}\quad + \quad{\Delta\quad x}} \right)^{2} +}} \\{\left( {{{R \cdot \sin}\left( \quad{\frac{2 \cdot \pi}{\quad N} \cdot \left( {i\quad - \quad 1} \right)} \right)}\quad + \quad{\Delta\quad y}} \right)^{2} +} \\{\left( \quad{z_{\quad f}\quad + \quad{\Delta\quad z}} \right)^{2} - \left( {R^{\quad 2} + z_{\quad f}^{\quad 2}} \right)}\end{matrix} & (32)\end{matrix}$where Δx, Δy, and Δz are the small movements of the point from theoriginal position in three dimensions, d_(in) and d_(io), are the newand original distance to the interrogation point for the i^(th)transducer, and Z_(f) is the location of the focus. Equation 32 alsodescribes a system where all of the transducers are in the same plane ata radius ‘R’.

Equation (32) can be simplified to: $\begin{matrix}\begin{matrix}{{\frac{c_{tissue}^{2}}{8 \cdot \sqrt{R^{2} + z_{f}^{2}}} \cdot \begin{bmatrix}{t_{1n}^{2} - t_{1o}^{2} - {\frac{2}{c_{tissue}}\left( {{\Delta^{2}x} + {\Delta^{2}y} + {\Delta^{2}z}} \right)}} \\{t_{2n}^{2} - t_{2o}^{2} - {\frac{2}{c_{tissue}}\left( {{\Delta^{2}x} + {\Delta^{2}y} + {\Delta^{2}z}} \right)}} \\{t_{3n}^{2} - t_{3o}^{2} - {\frac{2}{c_{tissue}}\left( {{\Delta^{2}x} + {\Delta^{2}y} + {\Delta^{2}z}} \right)}}\end{bmatrix}} =} \\{\begin{bmatrix}a_{1\quad x} & a_{1\quad y} & a_{1\quad z} \\a_{2\quad x} & a_{2\quad y} & a_{2\quad z} \\a_{3x} & a_{3\quad y} & a_{3z}\end{bmatrix} \cdot \begin{bmatrix}{\Delta\quad x} \\{\Delta\quad y} \\{\Delta\quad z}\end{bmatrix}}\end{matrix} & (33)\end{matrix}$where C_(tissue) is the velocity of sound in tissue, t_(i)* is the totaltime to the interrogation point, and a_(im) are the components of theunit vectors for the respective transducers.

As equation (33) shows, solving for Δx, Δy, and Δz requires taking theinverse of the a-matrix or directional matrix. Therefore, it is criticalto accurately determine a_(im) if the motion is to be tracked properly.

One method to accurately determine the directional matrix is to mountthe system in a test station that offers precise control of x, y and zmovement. Next, the system is coupled to tissue mimicking material. Thestages are moved in x, y or z only in small increments that insures theposition can be tracked. For example, suppose that the stage is onlymoved in the x direction such that Δy and Δz are zero. Equation (33) canthen be simplified to the following: $\begin{matrix}{{\frac{c_{tissue}^{2}}{8 \cdot \sqrt{R^{2} + z_{f}^{2}}} \cdot \begin{bmatrix}{t_{1n}^{2} - t_{1o}^{2} - {\frac{4}{c_{tissue}^{2}}\left( {\Delta^{2}x} \right)}} \\{t_{2n}^{2} - t_{2o}^{2} - {\frac{4}{c_{tissue}^{2}}\left( {\Delta^{2}x} \right)}} \\{t_{3n}^{2} - t_{3o}^{2} - {\frac{4}{c_{tissue}^{2}}\left( {\Delta^{2}x} \right)}}\end{bmatrix}} = \begin{bmatrix}{{a_{1\quad x} \cdot \Delta}\quad x} \\{{a_{2\quad x} \cdot \Delta}\quad x} \\{{a_{3\quad x} \cdot \Delta}\quad x}\end{bmatrix}} & (34)\end{matrix}$

Since Δx is known, equation (34) can be solved for the x component ofthe unit vector: $\begin{matrix}{{\frac{c_{tissue}^{2}}{{8 \cdot \Delta}\quad{x \cdot \sqrt{R^{2} + z_{f}^{2}}}} \cdot \left( {t_{1\quad n}^{2} - t_{1\quad o}^{2} - {\frac{4}{c_{tissue}^{2}} \cdot \left( {\Delta^{2}x} \right)}} \right)} = a_{1\quad x}} & \left( {35a} \right) \\{{\frac{c_{tissue}^{2}}{{8 \cdot \Delta}\quad{x \cdot \sqrt{R^{2} + z_{f}^{2}}}} \cdot \left( {t_{2\quad n}^{2} - t_{2\quad o}^{2} - {\frac{4}{c_{tissue}^{2}} \cdot \left( {\Delta^{2}x} \right)}} \right)} = a_{2\quad x}} & \left( {35b} \right) \\{{\frac{c_{tissue}^{2}}{{8 \cdot \Delta}\quad{x \cdot \sqrt{R^{2} + z_{f}^{2}}}} \cdot \left( {t_{3\quad n}^{2} - t_{3\quad o}^{2} - {\frac{4}{c_{tissue}^{2}} \cdot \left( {\Delta^{2}x} \right)}} \right)} = a_{3\quad x}} & \left( {35c} \right)\end{matrix}$

Equations (35a), (35b) and (35c) show how the x components can easily becalculated from the acquired data. By making many Δx movements, anaverage and standard deviation of a_(1x), a_(2x), and a_(3x) can becalculated. A similar approach can be done to calculate a_(iy) anda_(iz). This technique is also not limited to the number of transducersin the

In order to show the advantages using the calibration procedure, datafrom a 4 piston was acquired at 0 degrees, 120 degrees and 240 degreesalong an approximately 40 mm radius. The piston was coupled into an agarphantom set on a three dimensional motion stage. The phantom wasseparately moved in x, y and z in 0.25 mm

For the mechanical system, the directional matrix can be calculated asin Table 1. TABLE 1 Calculated original a direction matrix. X Y ZMagnitude −0.707 0.000 0.707 1.000 0.354 −0.612 0.707 1.000 0.354 0.6120.707 1.000

FIG. 25 depicts three graphs showing the correlation between actualposition and that determined using the algorithm described above for X,Y, and Z coordinates, pectively. The ideal result of one-to-onecorrelation is plotted as a line of slope 1. distances determined usingthe algorithm are plotted as points. The error increases for largemovements.

If the directional matrix is calculated using equations 35a, 35b and35c, then the directional matrix is as indicated in Table 2. TABLE 2Measured a direction matrix. X Y Z Magnitude −0.7315 0.0116 0.8836 1.1470.3638 −0.6372 0.6468 0.978 0.3908 0.6218 0.6487 0.980

Table 2 shows that the magnitude is not necessarily equal to one and thecomponents are significantly different than the mechanical predictions.FIG. 26 depicts three graphs showing that by using the Table 2 matrix,the algorithm results in improved tracking of movement. For example, a 1mm movement in the x dimension is measured as a movement of over 1.05 mmusing the standard mechanically determined directional matrix (FIG. 25),an error of over 5%. However, if the unit vector components arecalculated, then a 1 mm movement is measured to be 1.00 mm with an errorof less than 1% (FIG. 26). The significant reduction in error reducesthe possibility of accumulation error when re-referencing occurs.

Some embodiments include a station keeping system for executing theprocedures described above. The system may include multiple transducers,analog transmit and receive channels, an optional transmit and receivebeamformer, an optional multiplexer, an analog to digital board, a CPUand memory, and an electronic compass. In some embodiments, the systemprovides for the measurement of six degrees of freedom to uniquelyidentify any point in space. In some embodiments, the system isconfigured to provide multiple solutions by tracking a point andcalculating the effects due to translation and rotation. In addition, insome embodiments, the system provide for minimization of re-referencingby storing previous reference data with the x, y and z locations

Generally, using ultrasound for station keeping is not sensitive toazimuth rotation unless multiple points in a plane are tracked.Accordingly, in some embodiments, another technique may be used toacquire the azimuth, elevation and roll angles of the applicator at thebeginning of motion estimation as well as for future data acquisition.

FIG. 27 shows a block diagram of one embodiment of a motion estimationsystem. The ultrasound transducers 200 include at least three separatetransducers that are able to point at a common point. The transducers200 can include pistons, linear arrays, 1.5-D arrays as well as 2-Darrays. For example, in one embodiment, three phased arrays 202 can beused to focus at multiple points along a central line (e.g., the Z axis)as shown in FIG. 28. In this case, the center of each phased array 202is a distance ‘R’ from the origin of the x-y coordinate system. Thephased arrays 202 have length ‘L’ and width ‘W’ with the imaging planebisecting the circle 204 of radius ‘R’. Therefore, the phased arrays 202track identical points along the z-axis (out-of-the-paper). In anotherembodiment, the transducers may consist only of pistons that aremechanically pointed to a common point. This reduces the systemcomplexity since each piston represents only one channel.

Referring back to FIG. 27, mechanically attached to the transducers 200(dashed line) is an electronic compass 206 that determines the rotationof the device prior to and during the motion estimation. This includesazimuth, elevation and roll. The compass 206 is used to properly trackthe x, y and z movement in the coordinate system of the device away froma target.

A multiplexer 208 may be optionally included if the number of transmitand receive channels is to be limited, for example, if the phased arraysin FIG. 29 consist of 32 elements each. If a multiplexer 208 is notused, a minimum of 96 transmitters and 96 receivers may be used toaddress each element. However, if a 3:1 multiplexer is used, then only32 transmit and 32 receive channels are required, thereby reducingoverall cost.

The transmitter 210 may include a high voltage switch that excites thetransducer elements 200. Ideally, both positive and negative voltagesare available. Any available spectral shaping may also be beneficial tooptimizing the transmit pulse. The receiver 212 may include apreamplifier, filters, and other signal conditioning circuits prior todigitization.

Both the transmitter 210 and receiver 212 have an optional beamformer.The transmit beamformer 214 has only one delay profile per transmitevent whereas the receive beamformer 216 is digital and allowsbeamforming at multiple depths. A memory device 218 stores the digitizedsignal from each transducer. The number of signals stored peracquisition is equivalent to the number of transducers in the device.The memory 218 may also save previous reference frame information. Theinformation from the electronic compass 206 is also digitized for eachacquisition and stored in memory 218.

The CPU 220 orchestrates the timing throughout the system and places thecomponents in specific states. The CPU 220 also executes the trackingalgorithm.

FIG. 29 describes the process flow chart that may be used to acquire asignal data sed estimate the motion. It is assumed that a referencesignal data set has been acquired. The process flow chart can be splitinto two separate regions. The first is the acquisition area and thesecond is the algorithm. When the process is coded, a producer(acquisition)—consumer (calculation) model may be used to limitcomplexity and optimize processing time.

On the acquisition side, the first step (block 250) is to acquire theazimuth, elevation and roll angles from the electronic compass. Theseangles are used to calculate the distance moved relative to the currentreference frame and ultimately the starting location. It is beneficialto use averaging or other filtering techniques that remove anyacceleration componenta.

Next, at block 252, the signal vectors are acquired from the transducersin either a pulse-echo or pitch-catch mode. It may be necessary to resetthe multiplexers depending on the system hardware configuration for eachtransmit. Signal data may be acquired at multiple locations or averagedto reduce phase error. This step is repeated through decision block 254until the signal pulses from each transducer are acquired. In theembodiment depicted in FIG. 29, the number of transducers is 3, however,more transducers may be used since redundancy decreases the possibilityof error.

After the current signal vectors are acquired, the signal vectors fromthe current referece frame are recalled from memory at block 256 andpassed to the RfUME (Radio Frequency Ultrasound Motion Estimate)algorithm, which operates at block 258. The RfUME algorithm finds thephase change between the current signal vectors and the reference. Acorrelation technique such as sum of absolute differences (SAD) may beused to find the best match for each vector pair. This time differenceis used in the RfUME algorithm to calculate the total movement in x, yand z from the reference. Along with the movement, the RfUME algorithmassesses the quality of the fit. If SAD is used to determine the bestfit, a higher SAD value implies a lower quality fit. A histogramanalysis of SAD shows that the SAD magnitude predicts whether a motionestimate from the RfUME algorithm is good or bad. For example, if theSAD value is below a certain amount, then the measured phase differencefor that transducer is good. If it is above a certain amount, then themeasured phase difference may be good or bad. This SAD value is definedas the critical SAD.

Therefore, after the RfUME algorithm calculates the motion, the SADvalues (one SAD value for each transducer) are also compared to thecritical SAD at decision block 260. If the SAD values for any of thetransducers are greater than the critical SAD, then this result suggeststhat the previous signal acquisition should have been the new reference.In this case, the previous measured x, y and z location is theaccumulated movement (block 262). In order to limit re-referencing whichmay accumulate a significant amount of error, the accumulated x, y and zlocation of the possible new reference is compared with all of thestored references at decision block 264. If the accumulated x, y and zposition is near an old reference and the SAD values are acceptable,then instead of using a new reference, an old reference is used at block266. This technique may be beneficial when trying to hold the devicestill and re-referencing error must be limited.

Regardless of whether a new reference or stored reference is used, theRfUME algorithm may be used at block 268 to calculate the movement andSAD values. Next, the SAD values may be compared to a SAD threshold atdecision block 270. This threshold is dependent on the sample rate ofthe process flow chart as well as the user model. For example, thehigher the sample rate, the closer the SAD threshold could be to thecritical SAD value. Furthermore, the faster a user might move given afixed sample rate, then the lower the SAD threshold. SAD thresholdprevents loss of tracking ability by updating the reference frame at anacceptable rate. Therefore, if the SAD values are greater than the SADthreshold, the calculated x, y and z location is the accumulatedmovement and the current signal data becomes the new reference at block272. Again, to limit the amount of re-referencing, the accumulated x, yand z position are compared to the stored reference positions atdecision block 274. If there is a close match and the SAD values areacceptable, then the stored reference is used rather than the newlyacquired signal vectors at block 276.

After the critical SAD and threshold SAD are tested, the amount ofmovement is compared to movement thresholds at decision block 278. Thesethresholds for x, y and z are based on the transducer position andperformance. For example, the wider the beam response for the individualtransducers, the longer the distances that can be tracked from thereference frame. Furthermore, the directional matrix, frequency andbandwidth also affect the tracking performance. If these movementthresholds are exceeded, then the movement is accumulated and thereference vectors are changed at block 272. This process continues untilit is no longer desired to track motion.

In the RfUME algorithm, the recursive solution is used to tracktranslation as well as rotation. In other words, movement from thereference position includes both translation and rotation (Equations36a-36c).X _(total) =X _(rotation) +X _(translation)  (36a)Y _(total) =Y _(rotation) +Y _(translation)  (36b)Z _(total) =Z _(rotation) +Z _(translation)  (36c)

RfUME only tracks the movement from the current reference frame.Therefore, it is possible to rotate between the current reference frameand the old reference frame such that the coordinate system axes aredifferent. The electronic compass helps account for this difference. Thegeneral equation is:X _(i0) =X _(k0) +S _(k0) ⁻¹ ·X _(ik)  (37)where X_(i0) is the distance from original reference to the currentposition, X_(k0) is accumulated distance from the original reference tothe current reference, S_(k0) is the rotation matrix (3×3) between thecurrent reference and the original reference, X_(ik) is the distancemeasured with the RfUME algorithm from the current reference to thecurrent sample. The rotation matrix is determined by the electroniccompass and calibration to the ultrasound transducer is required. Inorder to display the net movement, X_(i0) must be multiplied by thenegative of S_(i0), which is the rotation matrix between the currentsample and the original reference.

It is also possible to obtain the azimuth, elevation and roll angleswith the RfUME algorithm. This is accomplished by calculating thedistance from multiple points in tissue. For example, if multiple pointsare tracked along the z-axis for the transducer concept depicted in FIG.28, then the tip and tilt can be determined. Azimuth may be determinedby tracking multiple points in a plane parallel to the transducer face.

Returning to the discussion of the flowchart in FIG. 5, after initiatingstation keeping, the targeting catheter may be withdrawn at block 112.As previously noted, acoustic arterial hemostasis is more effectivewithout the presence of a catheter, guidewire or other structure presentat the arteriotomy. Thus, the targeting catheter 32 may be completelywithdrawn from the patient as illustrated in FIG. 7G while the userkeeps the compression of the therapeutic applicator 20 constant andkeeps the arteriotomy 30 targeted within the focus of the therapeuticapplicator 20 via station keeping. The user interface on the applicator20 may provide feedback to the user to aid in maintaining optimalcompression and station keeping.

Finally, at block 114 of the flow chart in FIG. 5, therapeutic energymay be applied from the applicator to cause hemostasis. The treatmentdepth and dose may be automatically calculated and administered afterhemostatic compression and arteriotomy targeting are achieved and thetargeting catheter has been withdrawn. FIG. 7H illustrates an energizedultrasonic therapeutic applicator 20 delivering a focused ultrasoundbeam near the arteriotomy 30. The partial absorbance of the ultrasoundenergy by the tissue 31 at the focus of the beam causes rapid heating ofthe tissue 31 near the arteriotomy 30. Without being bound by anyparticular theory or mode of action, it is believed that the heatdenatures the native perivascular collagen with subsequent formation ofan extensive fibrin network that covers the arteriotomy 30, therebysealing it closed. The duration of therapy may be any suitable periodsufficient to effect hemostasis. In some embodiments, a continuousapplication of therapeutic energy is used. In other embodiments, theapplication of therapeutic energy may be interrupted, for example toallow interim cooling or repositioning of the therapeutic energyapplicator 20. The ultrasound treatment dose in one embodiment takesapproximately 60 seconds.

As depicted in FIG. 30, during this dosing period, the user interfacelocated on the therapeutic applicator may display relevant informationsuch as the amount of compression 300, a targeting display 302 forkeeping the ultrasound focused on the arteriotomy, as well as a countdown clock 304 indicating when treatment will terminate. Upon completionof the dosing, a short period of tissue cooling may be allowed to occurwithout compression or applicator position being changed. Subsequently,the treatment may be concluded by the therapeutic applicator beingremoved from the patient's skin.

As described above, the targeting catheter may be used to locate theprecise position of the arteriotomy, such as by use of a targeting aid(e.g., an inflatable balloon) located on the targeting catheter. As noteabove, suitable targeting aids are not limited to balloons but mayinclude one or more arteriotomy locating sensor(s). Suitable arteriotomylocating sensor(s) include but are not limited to: i) acoustictransceivers capable of transmitting and receiving acoustic signals(such as Doppler), ii) self-heated thermistor-based probes for detectingthe arteriotomy location by discriminating conductive and convectiveenergy dissipation levels in the tissues and blood surrounding theprobe, and iii) use of piezoelectric materials self heatingcharacteristics to discriminate conductive and convective energydissipation levels in tissues and blood surrounding the probe.Additional descriptions for these three arteriotomy detection techniquesare provided below. Those of skill in the art will appreciate many otherpossible methods and sensors for determining whether a sensor (orarbitrary location on a catheter) is located within a blood vesselversus or within tissue.

One example of arteriotomy locating sensor(s) includes one or moreDoppler transducers as illustrated in the targeting catheter 310depicted in FIG. 31. This targeting catheter 310 has a soft flexible tip312 with one or more locating and targeting piezoelectric Dopplerdevices 314. Further up the catheter 310 is a Doppler compression sensor316 and a hub 318 located at the terminal end of the catheter 310.Within the hub 318 is a tuning (matching) circuit and a mechanical andelectrical connector allowing the targeting catheter 310 to bemechanically and electrically connected to the control system hardware.

The arteriotomy localization step may be accomplished by slowlywithdrawing the targeting catheter, thereby causing the arteriotomylocating sensor(s) (e.g., Doppler devices 314) to get closer to thearteriotomy. The sensor signal is monitored to determine when thearteriotomy locating sensor is proximate to the arteriotomy. In oneembodiment, the Doppler transducer(s) 314 may also emit an ultrasoundsignal which is received by ultrasound receivers or transducers locatedon the applicator to monitor the movement and position of the Dopplertransducer(s) 314, such as by using ATOF as described above.

FIG. 32 is a schematic illustrating one embodiment of a procedure thatmay be used for arteriotomy localization (AL) using the catheterdepicted in FIG. 31. In this illustration, the Doppler transducer isreferred to as a “CW beacon.” In one embodiment, the targeting catheter310 has a flexible construction to minimally distort the vessel positionrelative to the therapeutic applicator during targeting. Thus, in oneembodiment, as depicted in FIG. 31, it is preferred that the ALpositioning is accomplished only through pulling (i.e., not pushing).This pulling may be accomplished by a withdrawal motion using eithercontinuous movement or discrete incremental pulls. Pulling may beaccomplished through either a manual process or by a device implementinga controlled pull process of the targeting catheter 310. The speed andforce associated with the targeting catheter 310 withdrawal maneuver toachieve the AL position may allow for clinically practical manualdexterity and a reasonable time for AL positioning, especially whenusing manual pulling. In one embodiment AL position takes only severalseconds. In an alternative embodiment, a targeting catheter 310 may beused that is stiff enough to be both pushed and pulled into thearteriotomy locating position.

To guide the user to achieve accurate arteriotomy localizationplacement, specific vascular locations may be detected by thearteriotomy location sensor (e.g., Doppler transducer(s)) using analgorithm subsystem. Upon detection, this information may be translatedinto feedback presented to the user through the user interface locatedon the display of the handheld therapeutic applicator. In oneembodiment, depicted in FIGS. 33A-33C, a “Green Light/Yellow Light/RedLight” display may be utilized. After the targeting catheter hasinitially begun to be withdrawn, the arteriotomy locating subsystem candetect the arteriotomy locating sensor (e.g., Doppler transducer(s))passing into the “treatment volume,” defined approximately by the tissuecylinder having as it's top surface the footprint of the therapeuticapplicator. At this point, the user interface may display a “GreenLight” (FIG. 33A) to indicate to the user that the beacon has crossedinto the treatment region. While the user is pulling in the “GreenLight” state, the pull velocity can be monitored via ATOF and, viacommunication with the ATOF system, the AL algorithms can detect beaconwithdrawal velocities that may be too high (e.g., >3 mm/sec). Uponexceeding this velocity limit, the AL algorithm can trigger the userinterface to alert the user to slow down the withdrawal speed if theuser is using manual pulling. Once the AL subsystem detects thearteriotomy location sensor (e.g., Doppler transducer(s)) as havingreached an arteriotomy “proximity zone”, defined, for example, as 8 mmfrom the arteriotomy along the targeting catheter track, the statuslight will change to “Yellow” on the user interface to alert the user toslow down the withdrawal speed, as shown in FIG. 33B. The ATOF systemcan be used to monitor the withdrawal speed and alert the user to slowdown if the speed exceeds an appropriate value relevant to the proximityzone, for example, 1.5 mm/sec. Once the AL subsystem detects thearteriotomy location sensor(s) (e.g., Doppler transducer(s)) as havingachieved arteriotomy localization (the “AL Position”), defined as aposition at or a known distance from the centroid of the arteriotomy,with a tolerance on positioning of +/−1.0 mm, the status light willchange to “Red” on the user interface (as shown in FIG. 33C) to alertthe user or a targeting catheter puller device to stop the withdrawal ofthe targeting catheter.

Those of skill in the art will appreciate that other methods ofproviding feedback to a user to adjust the speed of catheter withdrawalmay be used. For example, the actual rate of withdrawal may be displayedto the user. In addition, audible signals may employed such as tones orvoice commands.

FIG. 34 is a schematic depicting the withdrawal of the targetingcatheter 310. The spatial relationship of the arteriotomy locatingsensor 322 (e.g., Doppler transducer(s)) relative to the arteriotomywhen at the arteriotomy localization position can be described by thedistance vector, L_(btis), that describes the distance between thearteriotomy locating sensor 322 and the centroid 324 of the puncturesite along the path of the targeting catheter and puncture track asshown in FIG. 34. The centroid 324 of the arteriotomy is defined as theintersection of the targeting catheter 310 axis and the middle of thefemoral artery wall at the puncture. If L_(btis) has a positive value,the arteriotomy locating sensor 322 (e.g., Doppler transducer(s)) ispositioned in the tissue track, whereas, if L_(btis) is negative thearteriotomy locating sensor 322 (e.g., Doppler transducer(s)) is withinthe artery lumen. If L_(btis)=0.0 the arteriotomy locating sensor 322(e.g., Doppler transducer(s)) resides precisely at the centroid 324 ofthe puncture site.

As shown in FIGS. 32 and 34, the arteriotomy locating sensor may includean acoustic transducer labeled “CW Beacon” 322. The localization stepmay be accomplished by using the beacon 322 Doppler shift signals, asprocessed and interpreted by the arteriotomy localizationhardware/software (a combination of system hardware and system softwareincorporating arterial localization specific algorithms). The “CWBeacon” 322 may transmit an acoustic signal and detect the Dopplershifted echo. The Doppler shift information is associated with motion atand near the arteriotomy, and the dominant motions yielding beacon 322position-relevant signal information are those associated with bloodflow (e.g., velocity, flow turbulence, blood flow direction relative tothe beacon 322 orientation, and blood pressure variations). The Dopplerprocessing used can either be based on non-directional or directional(In-Phase and Quadrature) modes. In addition, different frequencies canbe used to excite different beacon 322 vibrational modes, modifying thetissue and spaces interrogated for Doppler shift information.

Although it is anticipated that the Doppler signals of relevance willoccur in the audible portion of the spectrum, in one embodiment, theelectronic system user interface is able to inform and guide the user asto beacon 322 localization through either audible or non-audible(principally visual) cues. In this way, less user training andexperience will be required to achieve reliable arteriotomylocalization. Localization cues that are non-audible and thus notdependent on a user learning “targeting sounds” may be generated byhaving the Doppler signals be processed by the arteriotomy localizationhardware/software in a manner which can identify the acoustic signatureof the arteriotomy or other characteristic location near the arteriotomythat has a consistent and unique acoustic signature.

FIG. 35 displays one embodiment of a system that may be used fortargeting catheter placement. A targeting catheter transducer (“TATXCR”) 324 may be mounted on the targeting catheter. Ultrasonic send andreceive circuits (“T/R”) 326 and processing may be provided byprogrammable pulser 328, amplifier 330, and analog to digital converter332, through transmit/receive switch 326—all under control of aprocessor 334, which itself is capable of either CW or pulse waveDoppler processing (depending upon the embodiment). This exemplaryprocessing configuration will be used as the basis for describingseveral approaches to targeting catheter placement below. Each approachto targeting catheter placement generally follows a process wherein theoperator advances the targeting catheter into the body via an introducersheath or entry channel and positions it in the entry channel inresponse to user interface information.

Forward looking Doppler—FIG. 36 depicts the functionality of a techniqueemploying forward looking pulsed wave Doppler to measure the distance340 in front of the targeting catheter beacon 178 at which the arterialflow volume is located. Here, beacon 178 is pulsed at a relatively high(approximately in the range 3-8 MHz) frequency, projecting a narrowacoustic beam 198 axially and in front of beacon 178. The beacon 178detects the Doppler shifted echo of each pulse. The computer of FIG. 35executes range-gated analysis of the Doppler pulse, thus measuringdistance to the region of blood flow, 340. The user interface caninstruct the operator to position the beacon 178 at a pointcorresponding to the clearance location (CL), the place where the beacon178 is located outside of the region of insonification from the therapybeam. Accordingly, in some embodiments, the targeting beacon 178 mayremain in the body during application of therapy, providing desiredtargeting information to a user to assist the user in maintaining thefocal point of the therapeutic energy at the site of the arteriotomy 30.For example, the location of the beacon 178 relative to the therapeuticapplicator 20 along with the distance to flow volume 340 may be used todetermine the location of the arteriotomy 30 relative to the applicator20.

Alternatively, in systems with two (or more) beacons 178 located on thetargeting catheter, the geometric uncertainty created by stick anglevariation may be compensated for, assuming that an ATOF positioningsystem is in operation during the targeting catheter placement andlocation process. For example, referring to FIG. 36, the forward lookingDoppler distance desired for proper positioning is defined by:DISTANCE TO FLOW VOLUME=(V+Dw+F)/sin (alpha s)  Eq. 38

Side-looking Doppler—FIG. 37 illustrates another positioning alternativewherein pulsed wave Doppler transmitted in a beam 342 perpendicularly tothe axis of the targeting catheter 32 locates the flow volume. In amanner similar to that employed in the forward looking Dopplertechnique, measurement of the distance to the flow volume 344 is madeand is used as a parametric representation of the location of beacon 178with respect to the Arteriotomy 30.

Z matching—In yet another alternative method illustrated in FIG. 38, atechnique is used which locates the beacon 178 relative to thearteriotomy 30 by matching the z coordinate (depth from the applicator20 surface positioned on the skin) of the beacon 178 to the z coordinateof the flow volume:Z FLOW VOLUME+DELTA=Z TA  Eq. 39where DELTA is an offset value representing the distance above the flowvolume desired for beacon positioning.

In this approach, the z coordinate of the beacon 178 is measured byutilizing the ATOF triangulation system—TOF distances 180 between thebeacon 178 and the receiving sensors 171 on the applicator 20. The zcoordinate of the anterior surface of the flow volume (shallowest) ismeasured, as depicted in FIG. 38, by pulsed Doppler ranging with pulsestransmitted by the therapeutic array in applicator 20 and received bybeacon 178. Because the therapeutic transducer may normally operate at asmall f/number, an interrogating Doppler line could be constructed froma number of transmit pulses having progressively varying focalpositions. This method offers very high resolution location of the flowvolume due to power available and the sharp focus.

In this technique, the applicator 20 would ideally be in targetedposition when executing the Z matching because the artery 28 may be deepat various positions. An iterative method of positioning may be usedwherein the applicator 20 is approximately positioned, beacon 178 isplaced, and then the applicator 20 and beacon 178 are re-positioned forfinal targeting.

Those of skill in the art will appreciate several alternative approachesfor utilizing a targeting catheter beacon 178 in combination with thesensors 171 on the therapeutic applicator 20. For example, in oneembodiment, a separate Doppler transducer (one or more channels) may beintegrated into the applicator 20 face and used to both send andreceive.

Combination Methods—It is noted that the above methods mayadvantageously also be used in combinations with each other, forexample, by combining forward looking and side-looking Doppler. Suchcombinations may be used to increase robustness of the positioningprocess. These methods may also be used in combination with thermalmethods. It is noted that beacons on the targeting catheter may be usedto make self-heated thermal measurement and associated positiondeterminations inside or outside of flowing blood. In this method, thecapacitance may be measured at an off resonant frequency of thepiezoelectric material (e.g. PZT) to estimate temperature.

In some embodiments, the arteriotomy location sensor on the targetingcatheter may be a thermistor based probe, used either alone or incombination with an ultrasound transducer. Use of self-heatingthermistors is termed herein as Thermistor Detection via Targeting andMonitoring (TDTM). These probes contain thermistors as sensors to assistin locating the puncture site, monitoring leakage of fluids or bleeding(prior to and during treatment), confirming the targeted location of thetherapeutic energy delivery, and measuring and monitoring at least aportion of the thermal dose delivered to the treatment field. In orderto be inserted down the puncture track, and thus directly into thepuncture wound at the vessel or body cavity, the TDTM probes may havephysical structures, and sizes, similar to catheterization guidewires.They can be deployed as an integral portion of a therapeutic hemostasisprocedure using either non-invasive or invasive therapeutic heatingmodalities, and have the advantage of requiring little additional effortor complexity in the puncture sealing or closure procedure.

The core sensor(s) deployed on the TDTM probes may be one or morethermistors (temperature sensors possessing the property of electricalresistance that varies with temperature). Both the electrical resistancevariation with temperature of thermistors and their property ofself-heating when supplied with adequate electrical power may beutilized. The latter property refers to the fact that when a thermistoris connected to an electrical circuit, power is dissipated in it as heatand, thus, the body temperature of the thermistor rises above thetemperature of its immediate environment. An energy balance on thethermistor requires that the rate at which energy is supplied (Q_(s))must equal the rate at which energy is lost, plus the rate at whichenergy is absorbed (energy storage). The rate of thermal energydelivered to the thermistor is equivalent to its electrical powerdissipation, i.e., Q_(s)=P=I²R=VI. The rate at which a thermistor'sthermal energy is lost to its surroundings (Q_(L)) is proportional tothe temperature difference between it and its surroundings, i.e.,Q_(L)=δ(T−T_(a)), where δ is the “dissipation coefficient.” Thedissipation coefficient is defined as the ratio, at a specifiedtemperature, of a change in the power dissipation of the thermistor tothe resultant thermistor body temperature change. The dissipationconstant depends on the thermal environment around the thermistor, sonaturally, the coefficient depends on the thermal conductivity of themedium surrounding it, convection (forced or free convection)influences, as may result from relative motion between the surroundingmedium and the thermistor, and thermal conduction through leads andsurfaces upon which the thermistor is mounted, etc. The dissipationcoefficient is also naturally dependent upon the physical geometry ofthe thermistor, especially its surface area and mass. For example, alarger surface area will result in a larger dissipation coefficient fora given thermal environment. This in turn requires more input power fora larger thermistor than a smaller one in order to achieve an equivalenttemperature difference between the thermistor and its surroundings. Theadditional power requirement effectively reduces the sensitivity of thedevice. Furthermore, a small thermistor device will have low thermalmass, which will allow it to cool and re-heat relatively quickly. Thisrelatively fast thermal response makes the smaller device more sensitiveto rapid changes in the dissipation coefficient.

It has been found that small self-heating thermistors, when placed inthe human body in medical procedures, can be used to measure tissuetemperature, thermal properties, blood temperatures and, whenappropriately calibrated, even blood flow levels in organs and vessels.Similar principles may be applied in detecting and discriminating levelsof blood flow at and surrounding the puncture wound site, and indiscriminating conduction and convective energy dissipation levels inthe tissues surrounding the probe. The TDTM probe may be positioned inthe tissue such that its thermistor sensor(s) can travel to and belocated in close proximity to the puncture site, typically through thepuncture track created by the instrument producing the puncture woundand/or maintaining the wound portal open (e.g., a catheter or needle).

FIG. 39 illustrates a TDTM probe having a single self-heating thermistor414 at the tip of the targeting catheter 32 inserted into an agar tissuephantom 418 incorporating a “blood vessel” 412 (duct cast into the agar)perfused with a blood-mimicking fluid (e.g., water in thermalequilibrium with the agar) 410.

The probe 414 may be placed in the vessel 412 in a manner analogous toarterial catheterization, by creating a puncture track from the “skin”surface down to the vessel puncture site (intersection of the probe 414with the vessel 412). By moving the probe 414 (probe) 414 travel isindicated as by arrows 416) in the puncture track, such that the sensor414 (e.g., the thermistor bead) can be alternatively placed a) in thetrack, b) at the anterior (upper) vessel wall (i.e., the puncture site)or c) in the lumen of the vessel 412, thermistor signals indicative ofthe bead location are provided as output to the data acquisition system.

FIG. 40 is a graph of temperature differential, show the variation ofthe differential for various locations of the probe. The thermistor maybe first “zeroed” with the bead in the track (i.e., the equilibriumtemperature whereby the self-heated thermistor is in the track and hasno flow may be set as the baseline). After zeroing, maneuvering theprobe in and out of the “vessel” will produce characteristic thermalsignals indicative of the bead position. For example, as the probe beadis advanced into the lumen of the vessel, the sensor signal indicatesthe associated cooling signature due to heat dissipation into the bloodflow (bead temperature decrease with characteristic flow-perturbationjitter in the temperature waveform). Subsequently, a withdrawal movementof the bead back toward the skin, pausing at the anterior (upper) wall,indicates an increased signal (higher temperature) associated with lessefficient cooling due to the flow boundary layer at the vessel wall. Inturn, as the probe is further withdrawn and the bead is returned to aposition just in the track (2 mm out of the lumem), the characteristicrelatively unperturbed temperature baseline waveform is againreproduced. Accordingly, the thermistor sensor has the ability toindicate when it is, alternatively, in the track (here above thevessel), in the lumen of the vessel, or at the wall of

The thermistor also has the ability to indicate when bleeding in thetrack occurs. FIG. 41 depicts a graph where blood mimicking flow (usingwater) is produced over the thermistor one drop at a time while the beadis in a track (small duct in thermal equilibrium with the agar and thefluid). As can be seen, the thermistor signal is extremely sensitive todetecting even discrete drops flowing over it. Thus, in principle, aTDTM probe having a thermistor bead in its shaft in the puncture trackshould be sensitive enough to detect any thermally significant trackbleeding, or bodily fluid leakage, from the puncture site.

When used in patients, the nature of the thermistor temperature signalswill change relative to the above results in phantoms, in large part dueto the pulsatile nature of blood flow in arteries and veins. Tocharacterize TDTM probe behavior under such conditions, arterialcatheterization wounds in pigs were studied. FIG. 42 shows theexperimental setup with the artery 412 located in the pig tissue 420 andthe vessel puncture site situated at 414, again using the single beadTDTM probe of FIGS. 39 through 41.

As shown in the graphs depicted in FIGS. 43A and 43B, when a thermistorbead is fully in the artery luminal blood flow, an oscillatory thermalsignal is produced of significant amplitude, indicative of the pulsatilechange in convective cooling surrounding the bead, i.e., the stop-startnature of the vessel blood flow accompanying the heart cycle (systole todiastole) of the animal. As the tip of the probe is drawn up to theanterior (upper) vessel wall and into the puncture wound in the vessel,the magnitude of the signal increases (more heating occurs), but theoscillation amplitude is diminished, both trends associated withdecreasing flow velocity next to the artery wall (poorer cooling due tothe wall boundary layer flow, exhibiting less flow fluctuation fromsystole to diastole) (see FIG. 43A). While translating the probe tip upinto the track just above the vessel wall, some pulsatile flow coolingis still present in the experiment, here due to only minimal tissuecompression being applied at this time. FIG. 43A indicates, however,that the event of compressing the tissue maximally (to the point whereno bleeding occurs in the track) can be faithfully reflected in thethermistor signal, as the equilibrium temperature rises to a maximum(conduction dominated thermal equilibrium normally associated with thebaseline zero temperature) and pulsatile oscillations (due to trackconvection) are extinguished.

Thus, TDTM probe thermistor beads can provide signal informationindicating when they reside either in the lumen of the vessel, near orat the vessel wall, or in the track, with either modest or significantcompression (i.e., indicating the presence or absence of trackbleeding). These properties can therefore be used to both place a TDTMprobe in the track such that the probe would be in a known relationshipto the puncture site, and in such a way that track bleeding could bemonitored, providing user feedback on level of tissue compression, withsuch information also being used to confirm absence of track bleeding,avoiding potentially compromising the efficacy of the cautery thermaldose via heat carried away in blood from the treatment zone.

As will be described below, the ability of placing the TDTM probe 428 infixed relationship to the puncture site can be useful in targeting thetherapeutic energy from a device used for deep cautery. One method toplace the probe at the puncture site is illustrated in FIG. 44 using aTDTM probe with two thermistor beads 430 and 432. Here the probe 428 isplaced such that its distal end beads 430 and 432 (separated by a smalldistance optimized for the application) straddle the puncture hole. Inthis case, the distal sensor 430 resides in the lumen of the artery 28,whereas the proximal bead 432 is in the track just above the puncture.The signals from the thermistors can be such that they can guide theclinician in positioning the probe 428 in this arrangement at thepuncture. The guidance in such positioning could be derived from eitherdirect operator observation and interpretation of the waveforms, orthrough a more automated, yet simple, user interface (e.g., oneemploying an algorithm that translates the waveform information intoautomatically interpreted symbolic information providing positioningcues).

FIG. 45 is a graph depicting sample temperature traces from an in vivopig experiment in which successful placement of the thermistor beadportion of the probe was placed in the artery in the arrangementrepresented in FIG. 44, i.e., dual beads were positioned to straddle thefemoral artery puncture.

Another embodiment includes a triple bead TDTM probe, as shown in FIG.46. In this embodiment, similar to FIG. 44, the distal bead 430 (nearestthe tip) would be placed in the lumen of the punctured vessel 28, whilethe proximal bead 432 is placed in the puncture track, thus bracketingthe puncture site. In this case, assuming bead separation distancesoptimized to the application, the third (center) bead 434 may be locatedapproximately at the puncture site. Deployed in this fashion, thethermistor beads could be used for guiding and confirming the placementof the therapeutic energy dose, for example, by simply delivering testexposures (shots) of therapeutic energy at the appropriate depth andpositioning the therapeutic beam using the feedback of the thermistorheating responses to maximize the heating response on the center bead.Those of skill in the art will appreciate that any number of thermistorsmay be employed to provide further precision in locating an arteriotomy.

To illustrate one method for guiding a therapeutic beam for targeting,FIG. 47 is graph showing the thermal responses from a dual bead TDTMprobe placed at the puncture site as in the case shown in FIG. 44, herein a pig femoral artery subjected to pulsed test shots of therapeuticenergy. The position of the beam focus and the probe thermistor beadsare simultaneously monitored using gray scale B-mode (2D) ultrasoundimaging. As shown, while using controlled movement of the hand-heldtherapeutic applicator, the position of the focus of the therapeuticbeam passes (in the plane of the 2D image) from bead #1 to bead #2. Thepath of the therapeutic beam focus is reflected in changes in amplitudeof the temperature spikes produced by the pulsed delivery of power asthe applicator targeting orientation and position is moved. Bymaximizing the temperature spike at the bead designated as the targetsensor, the energy can be appropriately targeted (while the TDTM probeis in place in the tissue puncture region).

In some embodiments, attempts to seal the puncture with the TDTM probein place (i.e., deployed through the puncture) is contraindicated due tothe tendency of the probe to either a) interfere with the sealingprocess during dosing, or b) disrupt a successful seal upon removal ofthe probe. Accordingly, in some embodiments, the probe is at leastpartially withdrawn until it is clear of the puncture prior to thedelivery of the dose. This maneuver will not eliminate the advantages ofthe probe. While in situ (at the puncture), the TDTM probe can be usedto position the therapeutic beam at the puncture, as described above.Further, the adequacy and level of the therapeutic dosing power can beassessed through the thermistor thermal signals in response to testpower pulses (as illustrated in FIG. 47) while the probe is in placeprior to dosing. Additionally, by withdrawing the TDTM probe just priorto dosing sufficiently to clear it from the puncture site, but with atleast one thermistor remaining in the puncture track, the probe can beused to monitor and guide compression and confirm the absence of trackbleeding.

It is also possible to use TDTM probe thermistors in conjunction withother sensors (non-thermistor) for targeting and monitoring the puncturesite. These “partner” sensors could be deployed on the shaft of theprobe used in the puncture track, and could provide complementary,redundant or unique information for orienting and guiding a medicaldevice of interest (e.g., a therapeutic device such as an ultrasoundapplicator used for sealing puncture wounds). FIG. 48 illustrates asystem where the probe contains two thermisters and one non-thermisterpartner sensor positioned in between. An example of complementaryinformation from the thermistor could include monitoring the state ofbleeding of the puncture track, while the partner sensor broadcasts itslocation for 3D positioning (e.g., by a distance measurement-based ortime-of-flight based triangulation method with appropriatereceiver-transmitter pairs, such as the ATOF technique described inabove). Such partner sensors could be based on a variety of energyforms, such as electrical, electromagnetic, magnetic, and acousticenergy, using appropriate transmission and receiver modules in thesensor and on the medical device being guided.

In some embodiments, a TDTM probe is used in conjunction with invasivetherapeutic devices used for sealing puncture wounds. FIG. 49illustrates a system where both thermister beads and a therapeutic heatsource are introduced to the puncture site. Such therapeutic heatingdevices could be placed down the puncture track, deployed ascatheter-like minimally invasive surgical (MIS) tools, and could havetheir sources of thermal energy delivery (therapeutic head) located attheir distal tip. A variety of energy sources could be possible withsuch MIS tools (e.g., RF electrical heating devices, therapeutic laserenergy delivered via fiber-optics or light wave-guides, microwaveantennae, ultrasound transducers, and the like). As for non-invasivehemostasis applicators, the invasive therapeutic devices can bepositioned in appropriate relation to the puncture site to effectivelytarget and seal the wound. The TDTM probe could be used to locate thetherapeutic head of the invasive sealing device at the puncture site byusing the TDTM probe as a guide-wire structure. In this configuration,the thermistor beads of the TDTM probe would be placed at the puncturesite, with the cautery device deployed over the TDTM probe and advancedtoward the puncture site until it reached a position that correspondedto an appropriate separation distance between the therapeutic head andthe puncture site. Prior to delivering the thermal dose, the TDTM probecould be withdrawn like a guidewire up into the inner channel of thecautery probe to remove the thermistor beads from the heated treatmentzone before the thermal dose is delivered to the puncture site. As forthe previously described TDTM probe concepts, the thermistor beads couldalso be used to confirm adequate compression at the treated site bymonitoring bleeding up the track of the MIS cautery device. In addition,the thermistor beads could be used to monitor the level of the delivereddose through the thermal response of the thermistor to therapeutic testdoses, as describe above.

In summary, the TDTM probe can be used in conjunction with bothnon-invasive and invasive thermal sealing or cautery therapeutic devicesin halting bleeding or bodily fluid leakage at depth from penetrationwounds associated with medical procedures. The TDTM probe can assist in:a) locating the puncture site (e.g., arteriotomy), and can be positionedin relationship to this site; b) confirming/guiding tissue compressionlevels adequate to eliminate track bleeding during application of thethermal dose; and c) targeting the therapeutic energy; d) assessing insitu the propriety of the therapeutic power In addition, the thermistorsensors can be used in combination and coordination with other types ofsensors, and in different configurations and spatial arrangements.Further more, the thermistor sensors can also be used to guide invasivetherapeutic devices (e.g., minimally invasive surgical type tools).Finally, TDTM probes with one, two, three or more sensors can be used,depending on the application and the procedural approach desired.

Although the invention has been described with reference to embodimentsand examples, it should be understood that numerous and variousmodifications can be made without departing from the spirit of theinvention. Accordingly, the invention is limited only by the followingclaims.

1. An arteriotomy targeting catheter, comprising: an arteriotomytargeting aid coupled to the catheter and adapted to detect the locationof an arteriotomy; and one or more beacons coupled to the catheterproximal to the arteriotomy targeting aid.
 2. The catheter of claim 1,wherein the arteriotomy targeting aid comprises an inflatable balloon.3. The catheter of claim 2, wherein the balloon comprises an elasticpolymeric material.
 4. The catheter of claim 3, wherein the soft elasticpolymeric material is selected from the group consisting of one or moreof a polyamide, a polyamide blend, a polyethylene, a polyethyleneterephthalate, a polyurethane, a polyamide, and a polyamide blend. 5.The catheter of claim 4, wherein the polyamide blend is PBAX.
 6. Thecatheter of claim 2, wherein the durometer of the balloon material isbetween 20A and 90D.
 7. The catheter of claim 6, wherein the durometerof the balloon material is between 80 A and 65 D.
 8. The catheter ofclaim 7, wherein the durometer of the balloon material is 90 A.
 9. Thecatheter of claim 1, wherein the arteriotomy targeting aid comprises amechanical expansible device.
 10. The catheter of claim 1, wherein thearteriotomy targeting aid comprises an arteriotomy locating sensor. 11.The catheter of claim 10, wherein the arteriotomy locating sensorcomprises a temperature sensor.
 12. The catheter of claim 11, whereinthe temperature sensor is a thermistor.
 13. The catheter of claim 10,wherein the arteriotomy locating sensor comprises a flow measurementsensor.
 14. The catheter of claim 10, wherein the arteriotomy locatingsensor comprises an optical sensor.
 15. The catheter of claim 10,wherein the arteriotomy locating sensor comprises an impedance sensor.16. The catheter of claim 10, wherein the arteriotomy locating sensorcomprises a Doppler sensor.
 17. The catheter of claim 1, wherein thebeacon comprises an ultrasonic transmitter.
 18. The catheter of claim 1,wherein the beacon comprises a radio frequency transmitter.
 19. Thecatheter of claim 1, wherein the beacon comprises a magnetic fieldgenerator.
 20. A method of determining the location of a therapeuticsite in a body, comprising: inserting a catheter into the body, whereinthe catheter comprises a targeting aid; and manipulating the cathetersuch that the targeting aid is adjacent to or at the therapeutic site.21. The method of claim 20, wherein the therapeutic site is anarteriotomy.
 22. The method of claim 20, wherein manipulating thecatheter comprises moving the catheter until a Doppler signal from thetargeting aid determines that the targeting aid is adjacent to or at thetherapeutic site.
 23. The method of claim 20, wherein the targeting aidcomprises a temperature sensor and manipulating the catheter comprisesmoving the catheter until the temperature sensor indicates that it isadjacent to or at the therapeutic site.
 24. The method of claim 20,wherein the targeting aid comprises a fluid flow detector andmanipulating the catheter comprises moving the catheter until the fluidflow detector indicates that it is adjacent to or at the therapeuticsite.
 25. The method of claim 20, wherein the targeting aid comprises anoptical sensor and manipulating the catheter comprises moving thecatheter until the optical sensor indicates that it is adjacent to or atthe therapeutic site.
 26. The method of claim 20, wherein the targetingaid comprises a pressure sensor and manipulating the catheter comprisesmoving the catheter until the pressure sensor indicates that it isadjacent to or at the therapeutic site.
 27. The method of claim 20,wherein the targeting aid comprises an impedance sensor and manipulatingthe catheter comprises moving the catheter until the impedance sensorindicates that it is adjacent to or at the therapeutic site.
 28. Themethod of claim 20, wherein the targeting aid comprises a force detectorand manipulating the catheter comprises moving the catheter until theforce detector indicates that it is adjacent to or at the therapeuticsite.
 29. The method of claim 20, wherein the targeting aid comprises amechanically expansive device and the method comprises expanding themechanically expansive device and moving the catheter until the deviceis adjacent to or at the therapeutic site.
 30. The method of claim 20,wherein the targeting aid comprises an inflatable balloon and the methodcomprises inflating the balloon and moving the catheter until theballoon is adjacent to or at the therapeutic site.
 31. The method ofclaim 20, wherein: the therapeutic site is an arteriotomy created by anintroducer sheath inserted into an artery; inserting the catheter intothe body comprises inserting the catheter and targeting aid through thelumen of the introducer sheath past the arteriotomy and into the artery;and manipulating the catheter comprises retracting the catheter suchthat the targeting aid approaches the arteriotomy.
 32. The method ofclaim 31, wherein the introducer sheath is retracted simultaneously withretraction of the catheter.
 33. The method of claim 31, wherein thetargeting aid comprises an inflatable balloon and wherein the balloon isinflated after insertion of the catheter and prior to retracting thecatheter.
 34. The method of claim 31, further comprising applyingcompression above the arteriotomy.
 35. A method of determining thelocation of a therapeutic site in a body relative to a therapeuticapplicator, comprising: inserting a targeting catheter into the body;identifying the location of the therapeutic site using the targetingcatheter; and determining the position of the targeting catheterrelative to the therapeutic applicator.
 36. The method of claim 35,wherein the therapeutic site is an arteriotomy.
 37. The method of claim35, further comprising aligning the therapeutic applicator with thetherapeutic site based on the relative position of the targetingcatheter.
 38. The method of claim 35, wherein determining the positionof the targeting catheter relative to the therapeutic applicatorcomprises using triangulation.
 39. The method of claim 38, wherein thetriangulation is based on magnetic fields.
 40. The method of claim 38,wherein the triangulation is based on acoustic signals.
 41. The methodof claim 40, wherein the triangulation is based on an acoustictime-of-flight determination.
 42. The method of claim 35, whereindetermining the position of the targeting catheter relative to thetherapeutic applicator comprises transmitting an ultrasound signal froma transmitter located on the catheter to multiple receivers located onthe therapeutic applicator.
 43. The method of claim 42, wherein thetransmitter comprises a piezoelectric cylinder.
 44. The method of claim42, wherein determining the position of the targeting catheter relativeto the therapeutic applicator comprises determining the acoustictime-of-flight from the transmitter to the receivers.
 45. The method ofclaim 35, wherein determining the position of the targeting catheterrelative to the therapeutic applicator comprises transmitting ultrasoundsignals from multiple transmitters located on the therapeutic applicatorto a receiver located on the catheter.